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Biodegradable Janus Nanoparticles for Local Pulmonary Delivery of Hydrophilic and Hydrophobic Molecules to the Lungs

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† Department of Pharmaceutics, Rutgers, The State University of New Jersey University, 160 Frelinghuysen Rd., Piscataway, New Jersey 08854, United States
‡ Department of Chemical and Biochemical Engineering, Rutgers, The State University of New Jersey, 98 Brett Road, Piscataway, New Jersey 08854, United States
*Phone: 732-445-2972; fax: 732-445-2581; e-mail: [email protected]
*Phone: 848-445-6348; fax: 732-445-3134; e-mail: [email protected]
Cite this: Langmuir 2014, 30, 43, 12941–12949
Publication Date (Web):October 9, 2014
https://doi.org/10.1021/la502144z

Copyright © 2014 American Chemical Society. This publication is licensed under these Terms of Use.

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Abstract

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The aim of the present work is to synthesize, characterize, and test self-assembled anisotropic or Janus particles designed to load anticancer drugs for lung cancer treatment by inhalation. The particles were synthesized using binary mixtures of biodegradable and biocompatible materials. The particles did not demonstrate cyto- and genotoxic effects. Janus particles were internalized by cancer cells and accumulated both in the cytoplasm and nuclei. After inhalation delivery, nanoparticles accumulated preferentially in the lungs of mice and retained there for at least 24 h. Two drugs or other biologically active components with substantially different aqueous solubility can be simultaneously loaded in two-phases (polymer-lipid) of these nanoparticles. In the present proof-of-concept investigation, the particles were loaded with two anticancer drugs: doxorubicin and curcumin as model anticancer drugs with relatively high and low aqueous solubility, respectively. However, there are no obstacles for loading any hydrophobic or hydrophilic chemical agents. Nanoparticles with dual load were used for their local inhalation delivery directly to the lungs of mice with orthotopic model of human lung cancer. In vivo experiments showed that the selected nanoparticles with two anticancer drugs with different mechanisms of action prevented progression of lung tumors. It should be stressed that anticancer effects of the combined treatment with two anticancer drugs loaded in the same nanoparticle significantly exceeded the effect of either drug loaded in similar nanoparticles alone.

Introduction

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Nanomedicine has been a growing branch of conventional medicine within the past decade. The variety of nanocarriers were developed and investigated for their medical applications including lipid-based formulations (liposomes, micelles, solid-lipid nanoparticles, etc.), and nonlipid-based formulations (dendrimers, mezoporous silica nanoparticles, etc.). (1-11) The diversity of shapes, sizes, and composition of nanoparticles allows for selecting the best suitable delivery vehicle for a specific application. For example, liposomes, self-assembled lipid vesicles have been successfully used for the delivery of different water-soluble therapeutic agents. (10, 12, 13) Micelles are typically used for the delivery of water-insoluble drugs carried because of their hydrophobic core. (14-17) Dendrimers, with a well-defined, regularly branched symmetrical structure and a high density of functional end groups at their periphery, have been used for the design of complex multifunctional drug delivery systems. (18-21) Mesoporous silica nanoparticles (MSNs) could also serve as suitable candidates for encapsulation and release of a variety of active pharmaceuticals due to their unique characteristics including a large surface area and high as well as uniform porosity. (22, 23) Recently, a promising new type of anisotropic nanoparticles—“Janus” particles—have been discovered and synthesized. These particles exhibited enormous potential as a drug delivery system due to their dual functionality and anisotropic nature. (24, 25) The beauty of these particles is that they can encapsulate in one complex system both hydrophobic and hydrophilic biologically active molecules. The encapsulation of dissimilar drugs into a two compartmental single particle allows for simultaneous delivery and release at the target site, thus avoiding problems with pharmacokinetics. Current technologies enable codelivery of two hydrophobic or two hydrophilic drugs, but generally not both. Anisotropic particles offer many additional advantages such as a larger surface area to volume ratio for optimizing targeting ligand and protective coating, the ability to incorporate imaging agents in a separate compartment to enable real-time tracking of treatment, and segregation of the active payloads. Their diverse shapes, sizes, and surfaces may represent additional advantages and offer a desired pharmacokinetics, body distribution, and pharmacodynamics. (26) It has also been shown that particles with complex local geometries are capable of preventing initial contact with incoming macrophages, thereby evading fast clearance by the reticuloendothelial system. (27)
For the past decade, our research group focused on the design, development, and application of different nanocarriers for the inhalation or intravenous delivery of hydrophilic and hydrophobic drugs for the efficient treatment of various diseases including several lung pathologies. (10, 11, 23) In terms of local inhalation delivery of therapeutics to the lungs, we found that the use of an appropriate nanocarrier can help to distribute the biologically active agents (drugs, nucleic acids, etc.) to the lungs and extend their retention period. This, in turn, can enhance the efficacy of the treatment and prevent possible adverse side effects upon healthy organs and tissues. (10, 11, 23)
We hypothesized that local delivery of several anticancer drugs with different aqueous solubility and mechanisms of action compartmentalized in Janus particles can provide their efficient delivery directly into the lungs, thus increase their accumulation in targeted cells and reduce adverse side effects on healthy organs by limiting drug concentration in the blood and healthy tissues. The present work was aimed at testing the hypothesis.

Materials and Methods

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Materials

Dichloromethane (DCM), Poly(lactic-co-glycolic acid) (PLGA) (MW 40 000–75 000; 65:35 lactic acid: glycolic acid), surfactants poly(vinyl alcohol) (PVA), sodium dodecyl sulfate (SDS), sodium dodecyl benzylsulfate (SDBS), phosphate buffered saline (PBS), Twin 20, N-hydroxysuccinimide (NHS), N-(3-(Dimethylamino)propyl)-N′-ethylcarbodiimide, Ethylmethanesulfonate (EMC), doxorubicin (DOX), curcumin (CUR), fluorescein isothiocyanate (FITC), and 4′,6-Diamidino-2-phenylindole dihydrochloride (DAPI) were purchased from Sigma-Aldrich (St. Louis, MO); The lipid, Precirol ATO 5 (glycerol distearate type I EP), was obtained from Gattefossé SAS (Saint-Priest Cedex, France); the near-infrared lipophilic dye, 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindotricarbocyanine iodide (DiR), was purchased from Invitrogen, Inc. (Grand Island, NY).

Cell Line

A549 human lung adenocarcinoma cells and A549 cells transfected with luciferase were obtained from the ATTC (Manassas, VA) and from Xenogen Bioscience, (Cranbury, NJ), respectively. Cells were cultured in RPMI 1640 medium (Sigma, St. Louis, MO) supplemented with 20% fetal bovine serum (Fisher Chemicals, Fairlawn, NJ) and 1.2 mL/100 mL penicillin–streptomycin (Sigma, St. Louis, MO). Cells were grown at 37 °C in a humidified atmosphere of 5% CO2 (v/v) in air. All experiments were performed on cells in the exponential growth phase.

Synthesis of Janus Particles and Loading with Drugs

For the in vitro and in vivo studies, Janus nanoparticles containing DOX and CUR were synthesized using a modified water-in-oil-in-water double emulsion solvent evaporation technique as previously described (Figure 1a). (25, 28) Briefly, 25 mg DOX were dissolved in 2 mL DI water to form the internal water phase. The oil phase consisted of 2.5% w/v polymer (PLGA) and lipid (Precirol ATO 5) in DCM at a 75:25 PLGA/Precirol ATO 5 mass ratio, along with 0.5% w/v Span 80 surfactant and 25 mg CUR. The internal water phase was emulsified with the oil phase using a Misonix Sonicator 3000 probe sonicator (QSonica, Newtown, CT) at an output power of 30 W for 30 s to form the primary W1/O emulsion. Then, 15 mL of aqueous surfactant solution (0.30% w/v PVA and 0.10% w/v SDBS) was poured into the W1/O emulsion and sonicated at an output power of 30 W for 30 s to produce a double W1/O/W2 emulsion. This solution was stirred at a constant speed of 125 rpm for at least 4 h at 40 °C in order to remove DCM. The resulting suspension was centrifuged for three 20 min cycles and washed with DI water to remove any residual free drugs and surfactants. The average DOX/CUR ratio for the nanoparticles containing both drugs was equal to 5:1. This ratio was optimized in the preliminary in vitro experiments for the most effective killing of lung cancer cells. Janus particles containing DOX only were prepared using the protocol described above, except CUR was not included in the oil phase. Previous studies have shown that the amount of residual dichloromethane remaining in nanoparticles prepared using the solvent evaporation method is negligible (<15 ppm). (29-31) Guidelines established by USP 30 limit the acceptable amount of residual dichloromethane present in drug substance, excipients, and products to 600 ppm. (32) However, if there is a toxicity concern, a Class 3 solvent such as ethyl acetate can be used instead of dichloromethane. We have synthesized these particles using ethyl acetate as the organic solvent.

Figure 1

Figure 1. Anisotropic biodegradable biphasic polymer/lipid Janus nanoparticles. (a) Schematic of the formation process of PLGA/Precirol Janus particles: (1) Internal aqueous phase containing the hydrophilic drug is emulsified in the oil phase containing the hydrophobic drug and immiscible polymer/lipid species; (2) The primary W/O emulsion is emulsified in aqueous surfactant solution; (3) Solvent evaporation induces phase separation of the polymer and lipid, resulting in bicompartmental Janus particles. (b–d) Representative optical (b), scanning electron (c), and fluorescence (d) microscope images are shown. (b) Oil droplets in the later stages of DCM evaporation showing phase separation of PLGA-curcumin and Precirol-DOX during particle formation; (c) Polymer/lipid combinations yielded “ice cream cone” shaped particles. (d) Polymeric phase of nanoparticles was labeled with FITC (green fluorescence); and lipid phase was labeled with DiR (red fluorescence).

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Janus particles containing CUR only were synthesized using a single oil-in-water emulsion template, as previously described. (25) A solution containing 2.5% w/v PLGA/Precirol ATO 5 and 25 mg of curcumin in DCM comprised the oil phase; 0.30% w/v PVA and 0.10% w/v SDBS aqueous solution was the water phase. The oil phase was added to the water phase and emulsified using sonication, followed by evaporation of the organic solvent.
For separate optical and fluorescent microscopic studies, larger microscale particles were used. For synthesis of these particles described above procedure was used. However, in this case, the two-phase mixture system was emulsified by manual agitation instead of sonication. Applying fewer shears resulted in significantly larger emulsion droplets and ultimately larger particles. The larger droplets required longer evaporation times, approximately 6 h on average.

Particle Size, Zeta Potential, Cytotoxicity and Genotoxicity

The particle size distribution and zeta potential were measured by Malvern ZetaSizer NanoSeries (Malvern Instruments, U.K.) according to the manufacturer’s instructions. All measurements were carried out at room temperature. Each parameter was measured five times for each batch, and average values and standard deviations were calculated. Laser diffraction was also used in addition to the ZetaSizer to measure particle size. Results obtained using laser diffraction were similar to those from proton correlation spectroscopy (PCS) and as such were not included in the manuscript to avoid repetition. Cytotoxicity of Janus nanoparticles (450 nm) was analyzed using a modified3-(4,5-dimethylthiazol-2-yl)-(2,5-diphenyltetrazolium bromide) (MTT) assay within 24, 48, and 72 h as previously described. (9) Briefly, 10 000 A-549 human lung cancer cells were incubated separately in 96-well microtiter plate with different concentrations of empty Janus nanoparticles (2–20 mg/mL), free nonbound DOX (0.0003–0.65 mg/mL), Janus nanoparticles with CUR (0.00004–0.35 mg/mL), Janus nanoparticles with DOX (0.0002–1.75 mg/mL), Janus nanoparticles with CUR (0.00004–0.35 mg/mL), and DOX (0.0002–1.75 mg/mL). Different concentrations of particles were used to select a noncytotoxic dose of nanoparticles that provide for survival of 100% cells. This concentration of nanoparticles was used in all future experiments with both drugs.
Genotoxicity of the studied particles were evaluated using the in vitro micronucleus assay as previously described. (9) Briefly, about 3000 cells were cultured with the media in 25 cm2 flasks and held 24 h before treatment. They were then incubated with particles for 24, 48, and 72 h. Negative control cells were incubated with fresh media, while positive control cells were treated with 400 g/mL ethylmethanesulfonate—EMC (positive control). After incubation, the cells were fixed in a cold solution of 100% methanol. The methanol was removed and the cells were washed with phosphate buffer and cell nuclei were then stained with 600 nM of DAPI for 8 min. This solution was removed and all the flasks were washed with PBS containing 0.05% Tween 20. After staining, the formation of micronuclei was detected by a fluorescent microscope (Olympus, New York, NY) and documented by counting the number of micronuclei per 1000 cells.

Synthesis of Labeled Polymer and Lipid

FITC-labeled PLGA was synthesized via the carbodiimide method. (33) Briefly, 0.5 g PLGA was dissolved in 0.75 mL DCM. The carboxylate groups of PLGA were activated by the addition of 0.1 g NHS and 0.15 g N-(3-(Dimethylamino)propyl)-N′-ethylcarbodiimide to form PLGA-NHS. The reaction was stirred for 2 h. Separately, 0.6 g FITC was dissolved in 0.25 mL DCM and 0.25 mL pyridine. The FITC solution was added to the PLGA-NHS solution and stirred for 24 h, then quenched with 0.1 N HCl. The organic layer was extracted by DCM and washed with water. Following complete solvent evaporation, the solution was centrifuged for 20 min. The supernatant was discarded and the precipitate was washed with diethyl ether to obtain PLGA-FITC. The stained polymer was dried in a desiccator overnight and refrigerated until use.
Stock solution of a lipophilic tracer DiR was prepared by adding 4 mL DCM to the 0.01 g DiR (final concentration of 2.5 mg/mL). DiR-labeled Precirol was produced by first dissolving 0.5 g Precirol in 25 mL DCM. Next, 0.2 mL DiR solution was added to the lipid solution. The mixture was stirred overnight in a closed container. The DCM was then evaporated, leaving Precirol-DiR. The stained lipid was dried in a desiccator overnight and refrigerated for the further use.

Confocal and Scanning Electron Microscopy

Cellular internalization of Janus nanoparticles was monitored in A549 lung cancer cells by confocal microscopy as previously described. (9, 11, 23) Briefly, Polymeric (PLGA) phase of nanoparticle was labeled with FITC (green fluorescence), and lipid phase was labeled with DiR (red fluorescence). Cells were incubated with the particles for 24 h at 37 °C and red and green fluorescence images were photographed and digitally overlaid. Superimposition of images allows for detecting of colocalization of PLGA and lipid phases of nanoparticles (yellow color). Images observed by confocal microscopy (LSM 500; Carl Zeiss, Germany) using manufacturer image analyzer software.
Particle morphology was observed using a scanning electron microscope (SEM) type Amray 1830 I (SEMTech Solutions, North Billerica, MA). Samples were mounted onto metallic stabs with double-sided adhesive tape. Prior to imaging, samples were sputter coated with carbon using a Balzers SCD Sputter Coater.

Animals

Athymic nu/nu mice 6–8 weeks old were obtained from Taconic (Hudson, NY). All mice were maintained in microisolated cages under pathogen free conditions in the animal maintenance facilities of Rutgers, The State University of New Jersey. Veterinary care followed the guidelines described in the guide for the care and use of laboratory animals (AAALAC) as well as the requirements established by the animal protocol approved by the Rutgers Institutional Animal Care and Use Committee (IACUC).

Inhalations Exposure System

A one-jet Collison nebulizer (BGI Inc., Waltham, MA) operated at an aerosolization flow rate of 2 L/min using dry and purified air (Airgas East, Salem, NH) was used to aerosolize particles while an additional air flow of 2–3 L/min was introduced to dilute and desiccate the resulting aerosol according to the previously described procedure. (10, 11, 23, 34) Briefly, the Collison nebulizer was equipped with a precious fluid cup to minimize the amount of liquid needed for reliable aerosolization. Then, under slight positive pressure, the entire aerosol flow of 4–5 L/min entered a mixing box of the 5-port exposure chamber (CH Technologies, Westwood, NJ) and was distributed to each animal containment tube via round pipes (four out of five chambers were used in the experiments). Each containment tube was connected to the distribution chamber via a connector cone, which features a spout in its middle to deliver fresh aerosol to a test animal and round openings in its back for exhaled air. During the inhalation experiments, each tested animal was positioned in a containment tube so that the animal’s nose was at the spout, or ‘‘inhalation point”. The animal was held in place by a plunger. The air exhaled by the test animal escapes the connector cone via openings in the cone’s back and was exhausted.

Distribution of Janus Nanoparticles in Different Organs

The distribution of Janus nanoparticles (155 and 450 nm) labeled with DiR was examined in nude mice after intravenous or inhalation administration as previously described. (10, 11, 23) Intravenously administered volume was 100 μL for each formulation. For inhalation administration, the same volume (100 μL) of suspension was used for each mouse. Our previous estimates showed that each mouse received about 1.2 μg of the inhaled substance. (34) Each experimental group consisted of 6-10 mice. Animals were anesthetized with isoflurane and euthanized, 1 and 24 h after the treatment. Lungs, liver, spleen, heart, and kidneys were excised, rinsed in saline, and fluorescence was registered by IVIS imaging system (Xenogen Corporation, Alameda, CA). Images of each organ were scanned and total fluorescence intensity was calculated using the manufacturer software. The method allows a quantitative comparison of the concentration of the same fluorescent dye between different series of the experiments. The mass of all organs was measured and the fluorescence intensity was normalized by organ mass.

Orthotopic Lung Cancer Model, Imaging, and Treatment

A mouse orthotopic model of human lung cancer previously developed in our laboratory (10, 11, 23) was used in the current study. Briefly, A549 human lung adenocarcinoma epithelial cells (5–8 × 106) transfected with luciferase were resuspended in 0.1 mL of RPMI medium containing 20% fetal bovine serum, mixed with 5 μL of EDTA and administered intratracheally to the lungs of athymic nu/nu mice through a catheter. The development of tumor was monitored and tumor volume was calculated using different imaging systems in live animals as previously described. (10, 11) All imaging procedures were performed under inhalation anesthesia with isoflurane at a concentration of 4% for induction of anesthesia and 1–2% for maintenance. Mice were placed in prone position with isoflurane supplied via a nose cone. After the image data acquisition, the recovery time of the animals from anesthesia was usually less than 5 min. Optical imaging was performed using in vivo bioluminescent IVIS (Xenogen, Alameda, CA) and magnetic resonance imaging (MRI) was carried by 1TM2 whole body scanner (Aspect Imaging Shoham, Israel) systems as previously described. (11) In order to visualize cancer cells transfected with luciferase, luciferin was injected intraperitoneally in dose of 150 mg luciferin/kg of body weight 10–15 min before imaging. The treatment of animals started when the total volume of lung tumor reached approximately 50 mm3 (4–6 weeks after inoculation of cancer cells). The following series of experiments were carried out: (1) Untreated mice (control); (2) mice treated by inhalation with empty Janus nanoparticles; (3) mice treated by intravenous (i.v.) injection with free nonbound DOX; (4) mice treated by inhalation with Janus nanoparticles loaded with CUR; (5) mice treated by inhalation with Janus nanoparticles loaded with DOX; and (6) mice treated by inhalation with Janus nanoparticles loaded with two drugs—DOX and CUR. The dose of both drugs in all drug-containing formulations was 2.5 mg/kg for the single administration. This dose corresponds to the maximum tolerated dose (MTD) estimated in separate experiments based on animal weight change after the instillation of increasing doses of drug formulation. The dose that led to the decrease of mouse body weight by 15% was considered as the MTD. The animals were treated twice per week within 4 weeks. Body weight of each mouse was measured using the electronic balances every second day.

Statistical Analysis

Data were analyzed using descriptive statistics, single-factor analysis of variance (ANOVA), and presented as mean values ± the standard deviation (SD) from six to ten independent measurements. The comparison among groups was performed by the independent sample Student’s test. The difference between variants is considered significant if P < 0.05.

Results

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Particles Characterizations

Polymer/lipid Janus particles display an interesting and unique morphology (Figure 1). Specifically, these particles exhibited a longer, cone-shaped tail bound to a spherical polymer head (“ice cream cone” shape). Optical (Figure 1b), scanning electron (Figure 1c), and confocal (Figure 1d) microscope images showed clear phase separation of lipid/polymer particles. Ten batches of nanoparticles were produced and characterized. The size of nanoparticles used for in vitro and in vivo studies measured by different methods was 155 ± 10 and 450 ± 23 nm and characterized by a relatively narrow size distribution. The polydispersity index (PDI) was 0.29 ± 0.08 and 0.33 ± 0.18, respectively for smaller and larger nanoparticles, respectively (means ± S.D.). Figure 2 shows an example of size distribution of 450 nm nanoparticles before after nebulization that were used for in vivo treatment of animals by inhalation. The average surface charge (zeta potential) of PLGA/Precirol nanoparticles was equal to -15.22 ± 1.78 mV (means ± S.D.).

Figure 2

Figure 2. Size distribution of 450 nm Janus nanoparticles before and after nebulization. These particles were used for in vivo treatment of animals by inhalation. A representative size distribution pattern is shown.

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Cytotoxicity and Genotoxicity

Cytotoxicity of Janus nanoparticles was analyzed by a modified MTT assay (Figure 3a). The results indicated that empty nanoparticles did not affect viability of lung cancer cells in all studied concentrations. Further experiments did not show any signs of genotoxicity of these nanoparticles. We found that incubation of cells with empty Janus nanoparticles did not induce the formation of micro nuclei (Figure 3b,c). As expected, free nonbound DOX induced cell death in cancer cells and therefore cellular viability was decreased (Figure 3a). It should be noted that due to the very poor water solubility of CUR it was impossible to measure cell viability with the free nonbound drug. Binding of DOX to nanoparticles slightly but statistically significant (P < 0.05 when compared with free drug) enhanced its cytotoxicity. In contrast to DOX-loaded nanoparticles, CUR containing particles demonstrated considerably lower cytotoxicity in lung cancer cells. However, the decrease in cell viability after the incubation with CUR-loaded nanoparticles was statistically more pronounced (P < 0.05) when compared with empty nanoparticles. It should be stressed that the incubation of cells with the combination of two anticancer drugs with different mechanisms of action and solubility loaded into Janus nanoparticles demonstrated their synergistic effect. In fact, the viability of lung cancer cells decreased approximately in 5 times after their incubation with nanoparticles containing both drugs (Figure 3 a). This decrease in cell viability was statistically significant (P < 0.05) when compared both drug-nanoparticle formulations with empty nanoparticles, free DOX, and nanoparticles containing just one drug. It should be stressed that empty nanoparticles did not show any signs of cyto- and genotoxicity within all studied periods (24, 48, and 72 h).

Figure 3

Figure 3. Cyto- and genotoxicity of studied substances. (a) Viability of A549 human lung cancer cells. Cells were incubated within 24 h with following formulations: 1, Empty Janus nanoparticles, 2, Free nonbound DOX, 3, Janus nanoparticles with CUR, 4, Janus nanoparticles with DOX, 5, Janus nanoparticles with CUR and DOX. (b, c) Genotoxicity (formation of micronuclei) of Janus nanoparticles and corresponding controls. (b) Quantitative analysis of micronuclei formation. (c) Representative fluorescence microscopy images of cell incubated within 24 h with 6, Media (negative control), 7, EMS (positive control, and 8, Janus nanoparticles. Means ± SD are shown. *P < 0.05 when compared with empty nanoparticles; +P < 0.05 when compared with free DOX; †P < 0.05 when compared with nanoparticles with CUR; and ‡P < 0.05 when compared with nanoparticles with DOX.

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Cellular Internalization

Cellular internalization of Janus nanoparticles was evaluated using confocal microscopy. A-549 human lung carcinoma cells were incubated with particles labeled simultaneously with two fluorescent dyes: FITC (polymeric phase of particles) and DiR (lipid phase of nanoparticles) (Figure 4a, b). The results revealed that after 24 h of incubation, a substantial amount of Janus nanoparticles was detected in both cellular plasma and nucleus (Figure 4a). In order to demonstrate that nanoparticles were not adhered to the cellular surface and penetrated into the cells, we analyzed their distribution in different cellular layers from the top of the cells to the bottom of the cells (z-sections, Figure 4b). The data showed that intracellular distribution of Janus nanoparticles was very similar in different cell layers. Hence, the developed anisotropic carriers can potentially be used for administration of therapeutic agents with different solubility and preferential biological activity both in the cellular cytoplasm and nuclei.

Figure 4

Figure 4. Intracellular localization of anisotropic biodegradable polymer/lipid Janus nanoparticles. (a) Representative images of A549 human lung cancer cells incubated 24 h with nanoparticles: 1, Light; 2–4, Fluorescence; 2, Polymeric (PLGA) phase of nanoparticles was labeled with FITC (green fluorescence); 3, Lipid (precirol) phase was labeled with DiR (red fluorescence); 4, Superimposition of green and red fluorescence images shows colocalization of PLGA and lipid phases of nanoparticles (yellow color); and 5, Superimposition of light, green and red fluorescence images shows intracellular localization of nanoparticles. (b) Representative confocal microscopy (z-series, from the top of the cell to the bottom) images of A549 human lung cancer cells incubated for 24 h with anisotropic biodegradable polymer/lipid Janus nanoparticles. Polymeric (PLGA) phase of nanoparticles was labeled with FITC (green fluorescence); lipid (precirol) phase was labeled with DiR (red fluorescence). Superimposition of green and red fluorescence images shows colocalization of PLGA and lipid phases of nanoparticles (yellow color).

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Body Distribution

A Collison nebulizer connected to four-port, nose-only exposure chambers was used for inhalation delivery of drug-loaded nanoparticles. The measurement of nanoparticle size showed that nebulization did not influence significantly on the size and stability of nanoparticles (Figure 2). The results presented on Figure 5 revealed that 1 h after intravenous administration the distribution patterns of 155 nm (Figure 5a) and 450 nm (Figure 5b) Janus nanoparticles were similar to the preferential particle accumulation in mouse liver. However, slightly higher accumulation in the lungs was found for the larger nanoparticles. One hour after inhalation delivery, nanoparticles of both sizes were detected in the lungs (Figure 5c,d); however, the accumulation of nanoparticles with 450 nm in diameter was twice higher when compared with 155 nm nanoparticles. The analysis of the distribution profile of Janus nanoparticles 24 h after their intravenous administrations showed that the majority of nanoparticles of both sizes were found in the liver and kidneys, while no fluorescent signal was detected in lungs (Figure 5e,f). As was mentioned above, the accumulation of larger nanoparticles in the lungs 1 h after treatment was substantially higher when compared with smaller nanoparticles (Figure 5c,d). However, 24 h after inhalation, similarly to the intravenous administration, the 155 nm nanoparticles were found only in the liver and kidneys (Figure 5g). In contrast, larger nanoparticles were still detected in the lungs 24 h after inhalation and their content was comparable with that after 1 h after treatment (Figure 5d, h). On the basis of these results we selected Janus nanoparticles with the size of 450 nm for further inhalation treatment of mice with orthotopic lung cancer.

Figure 5

Figure 5. Distribution of anisotropic biodegradable polymer/lipid Janus nanoparticles in different organs 1 and 24 h after intravenous or inhalation administrations. Mean values for eight animals are presented.

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Lung Cancer Treatment

To create an orthotopic murine model of lung cancer, A549 human lung cancer cells were transfected with luciferase and injected intratracheally into the lungs of nude mice. The initial deposition of cancer cells in the lungs and the subsequent progression of the lung tumor were analyzed using different imaging systems (measuring the bioluminescence of transfected cancer cells by IVIS and MRI (Figure 6a,b) in live, anesthetized animals. After the tumor volume reached the size of approximately 50 mm3, mice were treated twice per week during 4 weeks by inhalation with different drug formulations of Janus nanoparticles (450 nm). The following series of treatments were carried out: (1) Untreated animals (control); (2) Inhalation treatment with empty nanoparticles; (3) Intravenous treatment with free nonbound doxorubicin; (4) Inhalation treatment with nanoparticles containing curcumin; (5) Inhalation treatment with nanoparticles containing doxorubicin; and (6) Inhalation treatment with nanoparticles containing curcumin and doxorubicin. Inhalation of mice with empty nanoparticles did not influence significantly on the size of lung tumor. In contrast, all types of inhalation treatment with nanoparticles containing drug(s) led to a substantial limitation of tumor progression (Figure 6c). Consistent with cytotoxicity data, nanoparticles loaded with DOX were more effective in terms of the suppression of tumor growth when compared with nanoparticles loaded with CUR. It should be noted that the concentrations of both drugs in all particle formulations used for the in vivo study was equal to 2.5 mg/kg for a single administration. In contrast, intravenous administration of free DOX only slightly suppressed tumor progression. However, the highest antitumor effect was achieved after inhalation with the nanoparticles simultaneously loaded with both drugs. This type of treatment almost completely prevented the progression of tumor. The measurements of body weight showed that the weight of untreated animals with tumor was significantly (P < 0.05) lower when compared with heathy mice without tumor (Figure 6d). Treatment with free DOX and nanoparticles with only one drug (CUR or DOX) partially prevent the weight loss. Combinatorial inhalation treatment with both drugs almost completely restored mouse weight (P > 0.05 when compared with heathy mice without tumor).

Figure 6

Figure 6. Suppression of lung tumor growth in mice inhaled with Janus nanoparticles containing anticancer drug(s). Representative optical (a) and magnetic resonance (b) images 4 weeks after tumor instillation. (c) Changes in lung tumor volume after beginning of treatment. (d) Body weight of mice at the end of experiment. (1), Healthy mice without tumor; (2), Untreated mice with tumor; (3–7), Mice with tumor treated with empty nanoparticles; (3), free DOX (4), nanoparticles with CUR (5), nanoparticles with DOX (6), and nanoparticles with CUR and DOX (7). *P < 0.05 when compared with healthy mice without tumor. +P < 0.05 when compared with untreated mice with tumor. The treatment of animals started when the total volume of lung tumor reached approximately 50 mm3 (4–6 weeks after inoculation of cancer cells). Mice were treated twice per week within 4 weeks. Means ± SD (n = 10) are shown.

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Discussion

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The presented study is aimed at developing and characterizing the biodegradable polymer/lipid anisotropic Janus nanoparticles in order to evaluate them as a potential drug delivery system for the treatment of lung cancer. The novel anisotropic particles were grown and self-assembled in large-batch, scalable, single-pot synthesis using a modified double emulsion-solvent evaporation technique. The primary advantage of the proposed particles is the presence of less and more hydrophilic parts in one particle simultaneously which allows for effective simultaneous loading of hydrophilic and lipophilic drugs. Such a strategy could be beneficial in treating many types of cancer that develop resistance to the same chemotherapeutic agent administered over time. It also may help in the use of two biologically active agents with different mechanism of action and synergism in treatment of different diseases including lung cancer.The synthesized nanoparticles had an “ice cream cone” like structure. Previously, we observed phase segregation of Precirol and PLGA or PCL into formation of such structures. (25) The formation behavior of these particles was entirely different in nature than that of the polymer/polymer particles. Rather than slow particle segregation analogous to cell division, the lipid Precirol “cone” precipitated long before the polymer component. Supersaturation of the lipid was reached much faster than that of the polymer, despite the lipid being present at significantly lower levels (25 wt % compared to 75 wt % of polymer). The lipid tail remained at the interface of the droplet as the spherical polymer component was formed.
During the study, we found that biodegradable Janus nanoparticles alone (without any drugs) did not demonstrate toxicity and did not induce formation of micro nuclei. Consequently, the synthesized nanoparticles themselves were neither cytotoxic nor genotoxic. These findings support the assumption that being injected systemically to the body Janus nanocarriers potentially would not produce additional toxic effect on organs and tissues during their degradation. The absence of cytotoxic effects makes these Janus nanoparticles an ideal candidate for the delivery of different drugs for treating various diseases in addition to cancer.
In vitro studies showed that the PLGA/Precirol Janus particles do not affect cell viability. Furthermore, when broken down to its individual components, the biodegradability of Janus particles is confirmed. PLGA is an FDA-approved, biodegradable polymer frequently used in drug delivery. (35-37) Precirol ATO 5 is an FDA-approved lipid frequently used in the production of solid lipid nanoparticles for drug delivery. (38) The surfactants PVA and SDBS are theoretically removed in the washing step. Although 100% removal is not possible, previous studies show that the amount of residual PVA associated with PLGA nanoparticles is proportional to the concentration of PVA used in the external aqueous phase. (39) For example, 0.5% w/v initial PVA concentration results in approximately 2% w/w residual PVA; whereas 5% w/v starting concentration resulted in approximately 5% w/w residual PVA. For the present study, a relatively low concentration of surfactant was used (0.4% w/v). PVA is considered a biodegradable polymer and is approved by the FDA for clinical use. (40, 41) SDBS is also biodegradable. (42) Consequently, one can consider the nanoparticles synthesized in the present study as biodegradable.
The next step in our study was dedicated to demonstrating that developed anisotropic carriers can penetrate lung cancer cells and release their active payloads providing a multipronged attack thus causing a more effective killing of the cells. The obtained results confirmed our hypothesis and showed that studied dual hydrophilic/hydrophobic nanoparticles were capable to penetrate the cells and successfully deliver their active components destroying almost 90% of cancer cells. It was also found that nanoparticles accumulate inside cells both in the cytoplasm and nuclei. This, in turn, allows for delivering drugs with cytoplasmic and nuclear mechanisms of action.
In order to proceed with the lung cancer treatment, the nanoparticles were nebulized and delivered into the mouse lungs by inhalation using the nose-only exposure chambers. The labeling of nanoparticles with a fluorescent dye allowed for studying the distribution profile of Janus particles with different sizes was studied. In particular, their ability to accumulate in the lungs of experimental animals after intravenous and inhalation administrations was analyzed. It was found that the combination of two important factors: size and route of administration, played the critical role in the Janus particles distribution profile. Particles with the diameter of 450 nm showed the highest accumulation and longest retention on the lungs after their inhalation delivery. The smallest particles probably faster penetrated into the bloodstream through alveoli-capillary barrier and therefore may be less effective in the treatment of lung diseases by inhalation and could potentially induce adverse side effects of treatment on healthy tissues. The retention of the nanoparticles in the lungs was studied within 24 h because it is known that all material which accumulates in the lungs is removed in about 24 h because of the cephalad movement of the mucus blanket. (43) The body distribution of Janus nanoparticles after inhalation is very similar to other types of particles with comparable sizes. In fact, liposomes, nanostructured lipid carriers and mesoporous silica nanoparticles with the size of 300-500 nm preferentially accumulated in the lungs after their administration by inhalation. (10, 11, 23, 44-46)
Thus, for further in vivo experiments in order to enhance the efficiency of cancer treatment and minimize adverse side effects of particles loaded with highly toxic anticancer drugs we proposed of using 450 nm nanoparticles and employing the local pulmonary route of administration by inhalation.
The selected nanoparticles loaded with doxorubicin and curcumin were tested using orthotopic murine model of human lung cancer. Intravenous injection of free nonbound doxorubicin was used as a model of currently used in clinic chemotherapeutic treatment protocol. Obtained results clearly demonstrated that local inhalation treatment of mice bearing lung tumors using Janus nanoparticles loaded with two anticancer drugs were able to successfully suppress the tumor growth. In contrast, the treatment of mice with free doxorubicin injected intravenously only slightly limited the growth of lung tumor. This result confirms the fact that simultaneous use of two drugs with different aqueous solubility and mechanisms of action is very beneficial for the success of cancer treatment. We also confirmed the synergism of these two drugs in accomplishing such high antitumor effect that cannot be achieved by treating the mice with the Janus particles containing only one drug. Consequently, dual chemotherapy with the proposed anisotropic Janus nanoparticles can be beneficial for treating of cancers that are resistant to the one particular drug or in enhancing the antitumor efficacy of an anticancer drug by coencapsulation with another drug or biologically active agent with synergetic effect. In the present study, we used doxorubicin and curcumin as model anticancer drugs in a proof-of-concept study. However, we cannot foresee obstacles for encapsulating any types of hydrophilic and hydrophobic drugs.

Conclusions

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The proposed anisotropic Janus nanoparticles have a high potential for the delivery of drugs with different physicochemical properties and can be used in chemotherapy of various types of cancers and treating other diseases. In particular, the present study confirmed their exceptional efficiency in local inhalation codelivery of hydrophilic and hydrophobic anticancer drugs and limiting the progression of lung cancer.

Author Information

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  • Corresponding Authors
    • M. Silvina Tomassone - Department of Chemical and Biochemical Engineering, Rutgers, The State University of New Jersey, 98 Brett Road, Piscataway, New Jersey 08854, United States;  Email: [email protected]
    • Tamara Minko - Department of Pharmaceutics, Rutgers, The State University of New Jersey University, 160 Frelinghuysen Rd., Piscataway, New Jersey 08854, United States;  Email: [email protected]
  • Authors
    • Olga B. Garbuzenko - Department of Pharmaceutics, Rutgers, The State University of New Jersey University, 160 Frelinghuysen Rd., Piscataway, New Jersey 08854, United States
    • Jennifer Winkler - Department of Chemical and Biochemical Engineering, Rutgers, The State University of New Jersey, 98 Brett Road, Piscataway, New Jersey 08854, United States
  • Notes
    The authors declare no competing financial interest.

Acknowledgment

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The work was supported in part by R01 grants CA111766 and HL118312 from the National Institutes of Health. We thank Dr. D. C. Reimer and Mr. V. Starovoytov for their help with the development and implementation of orthotopic mouse model of lung cancer and obtaining and providing analysis of transmission electron microscopy images, respectively.

References

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    Background: Treatment of late stage cancers has proven to be a very difficult task. Targeted therapy and combinatory drug administration may be the soln. Purpose: The study was performed to evaluate the therapeutic efficacy of PEG-PE micelles, co-loaded with curcumin (CUR) and doxorubicin (DOX), and targeted with anti-GLUT1 antibody (GLUT1) against HCT-116 human colorectal adenocarcinoma cells both in vitro and in vivo. Methods: HCT-116 cells were treated with non-targeted and GLUT1-targeted CUR and DOX micelles as a single agent or in combination. Cells were inoculated in female nude mice. Established tumors were treated with the micellar formulations at a dose of 4 mg/kg CUR and 0.4 mg/kg DOX every 2 d for a total of 7 injections. Results: CUR + DOX-loaded micelles decorated with GLUT1 had a robust killing effect even at low doses of DOX in vitro. At the doses chosen, non-targeted CUR and CUR + DOX micelles did not exhibit any significant tumor inhibition vs. control. However, GLUT1-CUR and GLUT1-CUR + DOX micelles showed a significant tumor inhibition effect with an improvement in survival. Conclusion: We showed a dramatic improvement in efficacy between the non-targeted and GLUT1-targeted formulations both in vitro and in vivo. Hence, we confirmed that GLUT1-CUR + DOX micelles are effective and deserve further investigation.
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    Sawant, R. R.; Jhaveri, A. M.; Koshkaryev, A.; Qureshi, F.; Torchilin, V. P. The effect of dual ligand-targeted micelles on the delivery and efficacy of poorly soluble drug for cancer therapy J. Drug Target 2013, 21, 630– 638
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    The effect of dual ligand-targeted micelles on the delivery and efficacy of poorly soluble drug for cancer therapy
    Sawant, Rupa R.; Jhaveri, Aditi M.; Koshkaryev, Alexander; Qureshi, Farooq; Torchilin, Vladimir P.
    Journal of Drug Targeting (2013), 21 (7), 630-638CODEN: JDTAEH; ISSN:1026-7158. (Informa Healthcare)
    We prepd. and evaluated transferrin (Tf) and monoclonal antibody (mAb) 2C5-modified dual ligand-targeted poly(ethylene glycol)-phosphatidylethanolamine micelles loaded with a poorly sol. drug, R547 (a selective ATP-competitive cyclin-dependent kinase inhibitor) for enhancement of targeting efficiency and cytotoxicity in vitro and in vivo to A2780 ovarian carcinoma compared to single ligand-targeted micelles. Micellar solubilization significantly improved the soly. of R547 from 1 to 800 μg/mL. The size of modified and non-modified micelles was 13-16 nm. Flow cytometry indicated significantly enhanced cellular assocn. of dual ligand-targeted micelles compared to single ligand-targeted micelles. Confocal microscopy confirmed the Tf receptor-mediated endocytosis of rhodamine-labeled Tf-modified micelles after staining the micelle-treated cells with the endosomal marker Tf-Alexa488. The optimized dual-targeted micelles enhanced cytotoxicity in vitro against A2780 ovarian cancer cells compared to plain and single ligand-targeted micelles. Interestingly, in vivo anti-tumor efficacy was more pronounced for the prepn. with a single-targeting ligand (Tf). The specific combination Tf and mAb 2C5 did not yield the expected increase in efficacy as was obsd. in vitro. This observation suggests that the relationships between targeting ligands in vivo could be more complex than in simplified in vitro systems, and the results of the optimization process should always be verified in vivo.
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    Shcharbin, D.; Shakhbazau, A.; Bryszewska, M. Poly(amidoamine) dendrimer complexes as a platform for gene delivery Exp. Opin. Drug Deliv. 2013, 10, 1687– 1698
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    Mignani, S.; El Kazzouli, S.; Bousmina, M.; Majoral, J. P. Expand classical drug administration ways by emerging routes using dendrimer drug delivery systems: a concise overview Adv. Drug Deliv Rev. 2013, 65, 1316– 1330
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    Najlah, M.; D’Emanuele, A. Synthesis of dendrimers and drug-dendrimer conjugates for drug delivery Curr. Opin Drug Discov. Devel. 2007, 10, 756– 767
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    Synthesis of dendrimers and drug-dendrimer conjugates for drug delivery
    Najlah, Mohammad; D'Emanuele, Antony
    Current Opinion in Drug Discovery & Development (2007), 10 (6), 756-767CODEN: CODDFF; ISSN:1367-6733. (Thomson Scientific)
    A review. Dendrimers constitute a class of polymers that possess a well-defined structure allowing the precise control of size, shape and terminal group functionality. Their utility has been explored for a wide range of pharmaceutical applications. There is growing interest in the design and synthesis of novel biocompatible dendrimers and a no. of novel dendrimer architectures are discussed in this review. Recently, there has also been interest in the design of drug-dendrimer prodrugs and several of these systems are described, with emphasis on how the properties of such carriers may be tailored via surface engineering.
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    Neerman, M. F.; Zhang, W.; Parrish, A. R.; Simanek, E. E. In vitro and in vivo evaluation of a melamine dendrimer as a vehicle for drug delivery Int. J. Pharm. 2004, 281, 129– 132
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    In vitro and in vivo evaluation of a melamine dendrimer as a vehicle for drug delivery
    Neerman, Michael F.; Zhang, Wen; Parrish, Alan R.; Simanek, Eric E.
    International Journal of Pharmaceutics (2004), 281 (1-2), 129-132CODEN: IJPHDE; ISSN:0378-5173. (Elsevier B.V.)
    Cell-based and acute and subchronic in vivo toxicity profiles of a dendrimer based on melamine reveal that this class of mols. warrants addnl. study as vehicles for drug delivery. In cell culture, a substantial decrease in viability was obsd. at 0.1 mg/mL. For the acute studies, mice were administered 2.5, 10, 40 and 160 mg/kg of dendrimer via i.p. injection. At 160 mg/kg, 100% mortality was seen 6-12 h after injection. For the other cohorts, blood chem. work revealed no renal damage was taking place at 48 h. Liver enzyme activity nearly doubled for the mice treated at 40 mg/kg suggesting hepatotoxicity. For the subchronic studies, three i.p. injections of 2.5-40 mg/kg of dendrimers were administered at 3-wk intervals. No mortality was obsd. Forty-eight hours following the last administration, blood chem. revealed no renal damage, but liver damage was indicated by elevated serum enzyme activity at the highest dose. Histopathol. data further confirms that doses up to 10 mg/kg show no hepatic damage at subchronic doses. However, subchronic doses at 40 mg/kg lead to extensive liver necrosis.
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    He, Q.; Shi, J. MSN anti-cancer nanomedicines: Chemotherapy enhancement, overcoming of drug resistance, and metastasis inhibition Adv. Mater. 2014, 26, 391– 411
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    MSN Anti-Cancer Nanomedicines: Chemotherapy Enhancement, Overcoming of Drug Resistance, and Metastasis Inhibition
    He, Qianjun; Shi, Jianlin
    Advanced Materials (Weinheim, Germany) (2014), 26 (3), 391-411CODEN: ADVMEW; ISSN:0935-9648. (Wiley-VCH Verlag GmbH & Co. KGaA)
    A review. In the anti-cancer war, there are three main obstacles resulting in high mortality and recurrence rate of cancers: the severe toxic side effect of anti-cancer drugs to normal tissues due to the lack of tumor-selectivity, the multi-drug resistance (MDR) to free chemotherapeutic drugs and the deadly metastases of cancer cells. The development of state-of-art nanomedicines based on mesoporous silica nanoparticle (MSNs) is expected to overcome the above three main obstacles. In the view of the fast development of anti-cancer strategy, this review highlights the most recent advances of MSN anti-cancer nanomedicines in enhancing chemotherapeutic efficacy, overcoming the MDR and inhibiting metastasis. Furthermore, we give an outlook of the future development of MSNs-based anti-cancer nanomedicines, and propose several innovative and forward-looking anti-cancer strategies, including tumor tissue-cell-nuclear successionally targeted drug delivery strategy, tumor cell-selective nuclear-targeted drug delivery strategy, multi-targeting and multi-drug strategy, chemo-/radio-/photodynamic-/ultrasound-/thermo-combined multi-modal therapy by virtue of functionalized hollow/rattle-structured MSNs.
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    Taratula, O.; Garbuzenko, O. B.; Chen, A. M.; Minko, T. Innovative strategy for treatment of lung cancer: targeted nanotechnology-based inhalation co-delivery of anticancer drugs and siRNA J. Drug Target 2011, 19, 900– 914
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    Innovative strategy for treatment of lung cancer: targeted nanotechnology-based inhalation co-delivery of anticancer drugs and siRNA
    Taratula, Oleh; Garbuzenko, Olga B.; Chen, Alex M.; Minko, Tamara
    Journal of Drug Targeting (2011), 19 (10), 900-914CODEN: JDTAEH; ISSN:1026-7158. (Informa Healthcare)
    A tumor targeted mesoporous silica nanoparticles (MSN)-based drug delivery system (DDS) was developed for inhalation treatment of lung cancer. The system was capable of effectively delivering inside cancer cells anticancer drugs (doxorubicin and cisplatin) combined with two types of siRNA targeted to MRP1 and BCL2 mRNA for suppression of pump and nonpump cellular resistance in non-small cell lung carcinoma, resp. Targeting of MSN to cancer cells was achieved by the conjugation of LHRH peptide on the surface of MSN via poly(ethylene glycol) spacer. The delivered anticancer drugs and siRNA preserved their specific activity leading to the cell death induction and inhibition of targeted mRNA. Suppression of cellular resistance by siRNA effectively delivered inside cancer cells and substantially enhanced the cytotoxicity of anticancer drugs. Local delivery of MSN by inhalation led to the preferential accumulation of nanoparticles in the mouse lungs, prevented the escape of MSN into the systemic circulation, and limited their accumulation in other organs. The exptl. data confirm that the developed DDS satisfies the major prerequisites for effective treatment of non-small cell lung carcinoma. Therefore, the proposed cancer-targeted MSN-based system for complex delivery of drugs and siRNA has high potential in the effective treatment of lung cancer.
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    Perro, A.; Reculusa, S.; Ravaine, S.; Bourgeat-Lami, E.; Duguet, E. Design and synthesis of Janus micro- and nanoparticles J. Mater. Chem. 2005, 15, 3745– 3760
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    Design and synthesis of Janus micro- and nanoparticles
    Perro, Adeline; Reculusa, Stephane; Ravaine, Serge; Bourgeat-Lami, Elodie; Duguet, Etienne
    Journal of Materials Chemistry (2005), 15 (35-36), 3745-3760CODEN: JMACEP; ISSN:0959-9428. (Royal Society of Chemistry)
    A review. Because the Roman god Janus was usually represented with two heads placed back to back, the term Janus is used for the description of particles whose surfaces of both hemispheres are different from a chem. point of view. So, they could be used as building blocks for supraparticular assemblies, as dual-functionalized devices, as particular surfactants if one hemisphere is hydrophilic and the other hydrophobic, etc. If they could allow the segregation of neg. charges on one hemisphere and pos. charges on the other one, they would display a giant dipole moment allowing their remote positioning by rotation in an elec. field as a function of field polarity. This review deals with the great and imaginative efforts which were devoted to the synthesis of Janus particles in the last fifteen years. A special emphasis is made on scalable techniques and on those which apply to the prepn. of Janus particles in the nanometer range. Specific properties and applications of Janus particles are discussed.
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    Romanski, F. S.; Winkler, J. S.; Riccobene, R. C.; Tomassone, M. S. Production and characterization of anisotropic particles from biodegradable materials Langmuir 2012, 28, 3756– 3765
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    Yoo, J. W.; Doshi, N.; Mitragotri, S. Adaptive micro and nanoparticles: Temporal control over carrier properties to facilitate drug delivery Adv. Drug Deliv Rev. 2011, 63, 1247– 1256
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    Champion, J. A.; Mitragotri, S. Role of target geometry in phagocytosis Proc. Natl. Acad. Sci. U. S. A. 2006, 103, 4930– 4934
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    Role of target geometry in phagocytosis
    Champion, Julie A.; Mitragotri, Samir
    Proceedings of the National Academy of Sciences of the United States of America (2006), 103 (13), 4930-4934CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
    Phagocytosis is a principal component of the body's innate immunity in which macrophages internalize targets in an actin-dependent manner. Targets vary widely in shape and size and include particles such as pathogens and senescent cells. Despite considerable progress in understanding this complicated process, the role of target geometry in phagocytosis has remained elusive. Previous studies on phagocytosis have been performed using spherical targets, thereby overlooking the role of particle shape. Using polystyrene particles of various sizes and shapes, we studied phagocytosis by alveolar macrophages. We report a surprising finding that particle shape, not size, plays a dominant role in phagocytosis. All shapes were capable of initiating phagocytosis in at least one orientation. However, the local particle shape, measured by tangent angles, at the point of initial contact dictates whether macrophages initiate phagocytosis or simply spread on particles. The local shape dets. the complexity of the actin structure that must be created to initiate phagocytosis and allow the membrane to move over the particle. Failure to create the required actin structure results in simple spreading and not internalization. Particle size primarily impacts the completion of phagocytosis in cases where particle vol. exceeds the cell vol.
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    Tomasini, M. D.; Zablocki, K.; Petersen, L. K.; Moghe, P. V.; Tomassone, M. S. Coarse grained molecular dynamics of engineered macromolecules for the inhibition of oxidized low-density lipoprotein uptake by macrophage scavenger receptors Biomacromolecules 2013, 14, 2499– 2509
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    Mainardes, R. M.; Evangelista, R. C. PLGA nanoparticles containing praziquantel: Effect of formulation variables on size distribution Int. J. Pharm. 2005, 290, 137– 144
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    PLGA nanoparticles containing praziquantel: effect of formulation variables on size distribution
    Mainardes, Rubiana M.; Evangelista, Raul C.
    International Journal of Pharmaceutics (2005), 290 (1-2), 137-144CODEN: IJPHDE; ISSN:0378-5173. (Elsevier B.V.)
    Praziquantel has been shown to be highly effective against all known species of Schistosoma infecting humans. Spherical nanoparticulate drug carriers made of poly(D,L-lactide-co-glycolide) acid with controlled size were designed. Praziquantel, a hydrophobic mol., was entrapped into the nanoparticles with theor. loading varying from 10 to 30% (wt./wt.). This study investigates the effects of some process variables on the size distribution of nanoparticles prepd. by emulsion-solvent evapn. method. The results show that sonication time, PLGA and drug amts., PVA concn., ratio between aq. and org. phases, and the method of solvent evapn. have a significant influence on size distribution of the nanoparticles.
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    Niwa, T.; Takeuchi, H.; Hino, T.; Kunou, N.; Kawashima, Y. In vitro drug release behavior of D,L-lactide/glycolide copolymer (PLGA) nanospheres with nafarelin acetate prepared by a novel spontaneous emulsification solvent diffusion method J. Pharm. Sci. 1994, 83, 727– 732
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    Ubrich, N.; Bouillot, P.; Pellerin, C.; Hoffman, M.; Maincent, P. Preparation and characterization of propranolol hydrochloride nanoparticles: A comparative study J. Controlled Release 2004, 97, 291– 300
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    Preparation and characterization of propranolol hydrochloride nanoparticles: a comparative study
    Ubrich, Nathalie; Bouillot, Philippe; Pellerin, Christina; Hoffman, Maurice; Maincent, Philippe
    Journal of Controlled Release (2004), 97 (2), 291-300CODEN: JCREEC; ISSN:0168-3659. (Elsevier)
    The water-in-oil-in-water (w/o/w) emulsification process is the method of choice for the encapsulation inside polymeric particles of hydrophilic drugs such as proteins and peptides which are high mol. wt. macromols. Our objective was to apply this technique in order to formulate nanoparticles loaded with both a hydrophilic and a low mol. wt. drug such as propranolol-HCl. Nanoparticles were prepd. using a pressure homogenization device with various polymers (poly-ε-caprolactone, poly(lactide-co-glycolide), ethylcellulose) and different amts. of drug and were compared in terms of particle size, encapsulation efficiency and drug release. Higher encapsulation efficiencies were obtained with both PCL (77.3%) and PLGA (83.3%) compared to ethylcellulose (66.8%). The in vitro drug release was characterized by an initial burst and an incomplete dissoln. of the drug. When decreasing the polymer/drug ratio, the release appeared more controlled and prolonged up to 8 h. It can be concluded that nanoparticles prepd. by w/o/w emulsification followed by solvent evapn. might be potential drug carriers for low mol. wt. and hydrophilic drugs.
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    Convention, U. S. P.USP 30; United States Pharmacopeial Convention , 2006.
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    Basu, S.; Harfouche, R.; Soni, S.; Chimote, G.; Mashelkar, R. A.; Sengupta, S. Nanoparticle-mediated targeting of MAPK signaling predisposes tumor to chemotherapy Proc. Natl. Acad. Sci. U. S. A. 2009, 106, 7957– 7961
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    Mainelis, G.; Seshadri, S.; Garbuzenko, O. B.; Han, T.; Wang, Z.; Minko, T. Characterization and application of a nose-only exposure chamber for inhalation delivery of liposomal drugs and nucleic acids to mice J. Aerosol Med. Pulm. Drug Deliv. 2013, 26, 345– 354
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    Characterization and Application of a Nose-Only Exposure Chamber for Inhalation Delivery of Liposomal Drugs and Nucleic Acids to Mice
    Mainelis, G.; Seshadri, S.; Garbuzenko, O. B.; Han, T.; Wang, Z.; Minko, T.
    Journal of Aerosol Medicine and Pulmonary Drug Delivery (2013), 26 (6), 345-354CODEN: JAMPC4; ISSN:1941-2711. (Mary Ann Liebert, Inc.)
    Background: A small nose-only exposure chamber was evaluated for inhalation delivery of drug carrier systems (DCSs) to mice for the treatment of lung cancer. The chamber then was used for inhalation delivery of an anticancer drug, antisense oligonucleotides (ASO), and small interfering RNA (siRNA) directly to the cancerous lungs of mice. Methods: The uniformity of particle delivery across the ports of the exposure chamber and stability of the DCS (liposomes) during continuous aerosolization by a Collison nebulizer were examd. The mean produced particle size by no. was approx. 130 nm, and the mass median diam. was approx. 270 nm. The system was then used to deliver DCS contg. doxorubicin (DOX) and ASO or siRNA targeted to multidrug resistance-assocd. protein 1 (MRP1) mRNA as suppressors of cancer cell resistance. The retention of the drug in the lungs and the effect on tumor size were compared after inhalation delivery and i.v. injection in a nu/nu mouse model of lung cancer. Results: The aerosol mass across the four inhalation ports had a coeff. of variation of less than 12%, and approx. 1.4% of the nebulized mass was available for inhalation at each port. The mean size of 130 nm of liposomal DCS did not change significantly during continuous 60-min aerosolization. For inhalation delivery of DCS with DOX+ASO/siRNA, the amt. of drugs available for inhalation was lower compared with i.v. injection of DOX; however, the obsd. lung dose and the retention time were significantly higher. The delivery of DOX+ASO/siRNA via inhalation resulted in tumor vol. redn. of more than 90%, whereas only about 40% redn. was achieved after i.v. injection of DOX. Conclusions: The investigated exposure system is suitable for inhalation delivery of complex DCS, and its use to deliver DCS contg. anticancer drugs and resistance suppressors via inhalation offered a superior method for lung cancer treatment in mice compared with i.v. injections.
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    Kumari, A.; Yadav, S. K.; Yadav, S. C. Biodegradable polymeric nanoparticles based drug delivery systems Colloids Surf., B 2010, 75, 1– 18
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    Biodegradable polymeric nanoparticles based drug delivery systems
    Kumari, Avnesh; Yadav, Sudesh Kumar; Yadav, Subhash C.
    Colloids and Surfaces, B: Biointerfaces (2010), 75 (1), 1-18CODEN: CSBBEQ; ISSN:0927-7765. (Elsevier B.V.)
    A review. Biodegradable nanoparticles were used frequently as drug delivery vehicles due to its grand bioavailability, better encapsulation, control release and less toxic properties. Various nanoparticulate systems, general synthesis and encapsulation process, control release and improvement of therapeutic value of nanoencapsulated drugs are covered in this review. The authors have highlighted the impact of nanoencapsulation of various disease related drugs on biodegradable nanoparticles such as PLGA, PLA, chitosan, gelatin, polycaprolactone and poly-alkyl-cyanoacrylates.
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    Makadia, H. K.; Siegel, S. J. Poly Lactic-co-glycolic acid (PLGA) as biodegradable controlled drug delivery carrier Polymers 2011, 3, 1377– 1397
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    Poly lactic-co-glycolic acid (PLGA) as biodegradable controlled drug delivery carrier
    Makadia, Hirenkumar K.; Siegel, Steven J.
    Polymers (Basel, Switzerland) (2011), 3 (3), 1377-1397CODEN: POLYCK; ISSN:2073-4360. (MDPI AG)
    A review. In past two decades poly lactic-co-glycolic acid (PLGA) has been among the most attractive polymeric candidates used to fabricate devices for drug delivery and tissue engineering applications. PLGA is biocompatible and biodegradable, exhibits a wide range of erosion times, has tunable mech. properties and most importantly, is a FDA approved polymer. In particular, PLGA has been extensively studied for the development of devices for controlled delivery of small mol. drugs, proteins and other macromols. in com. use and in research. This manuscript describes the various fabrication techniques for these devices and the factors affecting their degrdn. and drug release.
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    Sonaje, K.; Italia, J. L.; Sharma, G.; Bhardwaj, V.; Tikoo, K.; Kumar, M. N. V. R. Development of biodegradable nanoparticles for oral delivery of ellagic acid and evaluation of their antioxidant efficacy against cyclosporine A-induced nephrotoxicity in rats Pharm. Res. 2007, 24, 899– 908
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    Sahoo, S. K.; Panyam, J.; Prabha, S.; Labhasetwar, V. Residual polyvinyl alcohol associated with poly (d,l-lactide-co-glycolide) nanoparticles affects their physical properties and cellular uptake J. Controlled Release 2002, 82, 105– 114
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    Residual polyvinyl alcohol associated with poly (D,L-lactide-co-glycolide) nanoparticles affects their physical properties and cellular uptake
    Sahoo, Sanjeeb K.; Panyam, Jayanth; Prabha, Swayam; Labhasetwar, Vinod
    Journal of Controlled Release (2002), 82 (1), 105-114CODEN: JCREEC; ISSN:0168-3659. (Elsevier Science Ltd.)
    Polyvinyl alc. (PVA) is the most commonly used emulsifier in the formulation of poly lactide and poly(D,L-lactide-co-glycolide) (PLGA) polymeric nanoparticles. A fraction of PVA remains assocd. with the nanoparticles despite repeated washing because PVA forms an interconnected network with the polymer at the interface. The objective of this study was to det. the parameters that influence the amt. of residual PVA assocd. with PLGA nanoparticles and its effect on the phys. properties and cellular uptake of nanoparticles. Nanoparticles were formulated by a multiple emulsion-solvent evapn. technique using bovine serum albumin (BSA) as a model protein. The parameters that affected the amt. of residual PVA include the concn. of PVA and the type of org. solvent used in the emulsion. The residual PVA, in turn, influenced different pharmaceutical properties of nanoparticles such as particle size, zeta potential, polydispersity index, surface hydrophobicity, protein loading and also slightly influenced the in vitro release of the encapsulated protein. Importantly, nanoparticles with higher amt. of residual PVA had relatively lower cellular uptake despite their smaller particle size. It is proposed that the lower intracellular uptake of nanoparticles with higher amt. of residual PVA could be related to the higher hydrophilicity of the nanoparticle surface. In conclusion, the residual PVA assocd. with nanoparticles is an important formulation parameter that can be used to modulate the pharmaceutical properties of PLGA nanoparticles.
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    Garbuzenko, O. B.; Mainelis, G.; Taratula, O.; Minko, T. Inhalation treatment of lung cancer: The influence of composition, size and shape of nanocarriers on their lung accumulation and retention Cancer Biol. Med. 2014, 11, 44– 55
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    44
    Inhalation treatment of lung cancer: the influence of composition, size and shape of nanocarriers on their lung accumulation and retention
    Garbuzenko, Olga B.; Mainelis, Gediminas; Taratula, Oleh; Minko, Tamara
    Cancer Biology & Medicine (2014), 11 (1), 44-55CODEN: CBMADQ; ISSN:2095-3941. (Tianjin Medical University Cancer Institute and Hospital)
    Objective: Various nanoparticles have been designed and tested in order to select optimal carriers for the inhalation delivery of anticancer drugs to the lungs. Methods: The following nanocarriers were studied: micelles, liposomes, mesoporous silica nanoparticles (MSNs), poly propyleneimine (PPI) dendrimer-siRNA complexes nanoparticles, quantum dots (QDs), and poly (ethylene glycol) polymers. All particles were characterized using the following methods: dynamic light scattering, zeta potential, at. force microscopy, in vitro cyto- and genotoxicity. In vivo organ distribution of all nanoparticles, retention in the lungs, and anticancer effects of liposomes loaded with doxorubicin were examd. in nude mice after the pulmonary or i.v. delivery. Results: Significant differences in lung uptake were found after the inhalation delivery of lipid-based and non-lipid-based nanoparticles. The accumulation of liposomes and micelles in lungs remained relatively high even 24 h after inhalation when compared with MSNs, QDs, and PPI dendrimers. There were notable differences between nanoparticle accumulation in the lungs and other organs 1 and 3 h after inhalation or i.v. administrations, but 24 h after i.v. injection all nanoparticles were mainly accumulated in the liver, kidneys, and spleen. Inhalation delivery of doxorubicin by liposomes significantly enhanced its anticancer effect and prevented severe adverse side effects of the treatment in mice bearing the orthotopic model of lung cancer. Conclusion: The results of the study demonstrate that lipid-based nanocarriers had considerably higher accumulation and longer retention time in the lungs when compared with non-lipid-based carriers after the inhalation delivery. These particles are most suitable for effective inhalation treatment of lung cancer.
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  45. 45
    Garbuzenko, O. B.; Saad, M.; Betigeri, S.; Zhang, M.; Vetcher, A. A.; Soldatenkov, V. A.; Reimer, D. C.; Pozharov, V. P.; Minko, T. Intratracheal versus intravenous liposomal delivery of siRNA, antisense oligonucleotides and anticancer drug Pharm. Res. 2009, 26, 382– 394
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  46. 46
    Ivanova, V.; Garbuzenko, O. B.; Reuhl, K. R.; Reimer, D. C.; Pozharov, V. P.; Minko, T. Inhalation treatment of pulmonary fibrosis by liposomal prostaglandin E2 Eur. J. Pharm. Biopharm 2013, 84, 335– 344
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    Inhalation treatment of pulmonary fibrosis by liposomal prostaglandin E2
    Ivanova, Vera; Garbuzenko, Olga B.; Reuhl, Kenneth R.; Reimer, David C.; Pozharov, Vitaly P.; Minko, Tamara
    European Journal of Pharmaceutics and Biopharmaceutics (2013), 84 (2), 335-344CODEN: EJPBEL; ISSN:0939-6411. (Elsevier B.V.)
    Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and often fatal form of interstitial lung disease. We hypothesized that the local pulmonary delivery of prostaglandin E2 (PGE2) by liposomes can be used for the effective treatment of IPF. To test this hypothesis, we used a murine model of bleomycin-induced IPF to evaluate liposomal delivery of PGE2 topically to the lungs. Animal survival, body wt., hydroxyproline content in the lungs, lung histol., mRNA, and protein expression were studied. After inhalation delivery, liposomes accumulated predominately in the lungs. In contrast, i.v. administration led to the accumulation of liposomes mainly in kidney, liver, and spleen. Liposomal PGE2 prevented the disturbances in the expression of many genes assocd. with the development of IPF, substantially restricted inflammation and fibrotic injury in the lung tissues, prevented decrease in body wt., limited hydroxyproline accumulation in the lungs, and virtually eliminated mortality of animals after intratracheal instillation of bleomycin. In summary, our data provide evidence that pulmonary fibrosis can be effectively treated by the inhalation administration of liposomal form of PGE2 into the lungs. The results of the present investigations make the liposomal form of PGE2 an attractive drug for the effective inhalation treatment of idiopathic pulmonary fibrosis.
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    Figure 1

    Figure 1. Anisotropic biodegradable biphasic polymer/lipid Janus nanoparticles. (a) Schematic of the formation process of PLGA/Precirol Janus particles: (1) Internal aqueous phase containing the hydrophilic drug is emulsified in the oil phase containing the hydrophobic drug and immiscible polymer/lipid species; (2) The primary W/O emulsion is emulsified in aqueous surfactant solution; (3) Solvent evaporation induces phase separation of the polymer and lipid, resulting in bicompartmental Janus particles. (b–d) Representative optical (b), scanning electron (c), and fluorescence (d) microscope images are shown. (b) Oil droplets in the later stages of DCM evaporation showing phase separation of PLGA-curcumin and Precirol-DOX during particle formation; (c) Polymer/lipid combinations yielded “ice cream cone” shaped particles. (d) Polymeric phase of nanoparticles was labeled with FITC (green fluorescence); and lipid phase was labeled with DiR (red fluorescence).

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    Figure 2

    Figure 2. Size distribution of 450 nm Janus nanoparticles before and after nebulization. These particles were used for in vivo treatment of animals by inhalation. A representative size distribution pattern is shown.

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    Figure 3

    Figure 3. Cyto- and genotoxicity of studied substances. (a) Viability of A549 human lung cancer cells. Cells were incubated within 24 h with following formulations: 1, Empty Janus nanoparticles, 2, Free nonbound DOX, 3, Janus nanoparticles with CUR, 4, Janus nanoparticles with DOX, 5, Janus nanoparticles with CUR and DOX. (b, c) Genotoxicity (formation of micronuclei) of Janus nanoparticles and corresponding controls. (b) Quantitative analysis of micronuclei formation. (c) Representative fluorescence microscopy images of cell incubated within 24 h with 6, Media (negative control), 7, EMS (positive control, and 8, Janus nanoparticles. Means ± SD are shown. *P < 0.05 when compared with empty nanoparticles; +P < 0.05 when compared with free DOX; †P < 0.05 when compared with nanoparticles with CUR; and ‡P < 0.05 when compared with nanoparticles with DOX.

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    Figure 4

    Figure 4. Intracellular localization of anisotropic biodegradable polymer/lipid Janus nanoparticles. (a) Representative images of A549 human lung cancer cells incubated 24 h with nanoparticles: 1, Light; 2–4, Fluorescence; 2, Polymeric (PLGA) phase of nanoparticles was labeled with FITC (green fluorescence); 3, Lipid (precirol) phase was labeled with DiR (red fluorescence); 4, Superimposition of green and red fluorescence images shows colocalization of PLGA and lipid phases of nanoparticles (yellow color); and 5, Superimposition of light, green and red fluorescence images shows intracellular localization of nanoparticles. (b) Representative confocal microscopy (z-series, from the top of the cell to the bottom) images of A549 human lung cancer cells incubated for 24 h with anisotropic biodegradable polymer/lipid Janus nanoparticles. Polymeric (PLGA) phase of nanoparticles was labeled with FITC (green fluorescence); lipid (precirol) phase was labeled with DiR (red fluorescence). Superimposition of green and red fluorescence images shows colocalization of PLGA and lipid phases of nanoparticles (yellow color).

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    Figure 5

    Figure 5. Distribution of anisotropic biodegradable polymer/lipid Janus nanoparticles in different organs 1 and 24 h after intravenous or inhalation administrations. Mean values for eight animals are presented.

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    Figure 6

    Figure 6. Suppression of lung tumor growth in mice inhaled with Janus nanoparticles containing anticancer drug(s). Representative optical (a) and magnetic resonance (b) images 4 weeks after tumor instillation. (c) Changes in lung tumor volume after beginning of treatment. (d) Body weight of mice at the end of experiment. (1), Healthy mice without tumor; (2), Untreated mice with tumor; (3–7), Mice with tumor treated with empty nanoparticles; (3), free DOX (4), nanoparticles with CUR (5), nanoparticles with DOX (6), and nanoparticles with CUR and DOX (7). *P < 0.05 when compared with healthy mice without tumor. +P < 0.05 when compared with untreated mice with tumor. The treatment of animals started when the total volume of lung tumor reached approximately 50 mm3 (4–6 weeks after inoculation of cancer cells). Mice were treated twice per week within 4 weeks. Means ± SD (n = 10) are shown.

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      Nanoparticles for drug delivery in cancer treatment
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      Urologic Oncology: Seminars and Original Investigations (2008), 26 (1), 57-64CODEN: UOSOAA; ISSN:1078-1439. (Elsevier)
      A review. Nanoparticles (size in nanometer range) provide a new mode of cancer drug delivery functioning as a carrier for entry through fenestrations in tumor vasculature allowing direct cell access. These particles allow exquisite modification for binding to cancer cell membranes, the microenvironment, or to cytoplasmic or nuclear receptor sites. This results in delivery of high drug concns. to the targeted cancer cell, with reduced toxicity of normal tissue. Several such engineered drugs are in clin. practice, including liposomal doxorubicin and albumin conjugate paclitaxel. The carrier mediated paclitaxel has already shown significant efficacy in taxane resistant cancers, an approach highly relevant in prostate cancer, where taxanes are the treatment of choice. Other modifications including transferrin receptor and folate receptor targeted drug delivery mols. are in study. This new technol. provides many exciting therapeutic approaches for targeted high concn. drug delivery to cancer cells with reduced injury of normal cells.
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      Matsumura, Y. The drug discovery by nanomedicine and its clinical experience Jpn. J. Clin. Oncol. 2014, 44, 515– 525
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      Japanese journal of clinical oncology (2014), 44 (6), 515-25 ISSN:.
      It is expected that the incidence of various adverse effects of anticancer agents maybe decreased owing to the reduced drug distribution in normal tissue. Anticancer agent incorporating nanoparticles including micelles and liposomes can evade non-specific capture by the reticuloendothelial system because the outer shell of the nanoparticles is covered with polyethylene glycol. Consequently, the micellar and liposomal carrier can be delivered selectively to a tumor by utilizing the enhanced permeability and retention effect. Presently, several anticancer agent-incorporating nano-carrier systems are under preclinical and clinical evaluation. Several drug delivery system formulations have been approved worldwide. Regarding a pipeline of clinical development of anticancer agent incorporating micelle carrier system, several clinical trials are now underway not only in Japan but also in other countries. A Phase 3 trial of NK105, a paclitaxel incorporating micelle is now underway. In this paper, preclinical and clinical studies of NK105, NC-6004, cisplatin incorporating micelle, NC-6300, epirubicin incorporating micelle and the concept of cancer stromal targeting therapy using nanoparticles and monoclonal antibodies against cancer related stromal components are reviewed.
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      Journal of Controlled Release (2014), 190 (), 556-562CODEN: JCREEC; ISSN:0168-3659. (Elsevier B.V.)
      A review. A wide variety of nanocarriers and particularly cancer nanomedicines activate the complement system, which is the first line of the innate immune defense mechanism. Complement activation may induce inflammatory responses, but such responses arising from uncontrolled complement activation could be life threatening. Accordingly, the role of complement in initiation of adverse reactions to particulate and polymer therapeutics is receiving increasing attention. Furthermore, the involvement of complement-activation products in promoting tumor growth has also been indicated. This could be of serious concern for development of cancer nanomedicines and cancer nanotechnol. initiatives. These concepts are reviewed with preliminary evidence that intra-tumoral accumulation of model long circulating nanoparticles could promote tumor growth.
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      Saadeh, Y.; Leung, T.; Vyas, A.; Chaturvedi, L. S.; Perumal, O.; Vyas, D. Applications of nanomedicine in breast cancer detection, imaging, and therapy J. Nanosci. Nanotechnol. 2014, 14, 913– 923
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      Drbohlavova, J.; Chomoucka, J.; Adam, V.; Ryvolova, M.; Eckschlager, T.; Hubalek, J.; Kizek, R. Nanocarriers for anticancer drugs—New trends in nanomedicine Curr. Drug Metab. 2013, 14, 547– 564
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      Drbohlavova, Jana; Chomoucka, Jana; Adam, Vojtech; Ryvolova, Marketa; Eckschlager, Tomas; Hubalek, Jaromir; Kizek, Rene
      Current Drug Metabolism (2013), 14 (5), 547-564CODEN: CDMUBU; ISSN:1389-2002. (Bentham Science Publishers Ltd.)
      This review provides a brief overview of the variety of carriers employed for targeted drug delivery used in cancer therapy and summarizes advantages and disadvantages of each approach. Particularly, the attention was paid to polymeric nanocarriers, liposomes, micelles, polyethylene glycol, poly(lactic-co-glycolic acid), dendrimers, gold and magnetic nanoparticles, quantum dots, silica nanoparticles, and carbon nanotubes. Further, this paper briefly focuses on several anticancer agents (paclitaxel, docetaxel, camptothecin, doxorubicin, daunorubicin, cisplatin, curcumin, and geldanamycin) and on the influence of their combination with nanoparticulate transporters to their properties such as cytotoxicity, short life time and/or soly.
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      Current Opinion in Biotechnology (2013), 24 (6), 1159-1166CODEN: CUOBE3; ISSN:0958-1669. (Elsevier B.V.)
      A review. In recent years, the use of nanomedicine formulations for therapeutic and diagnostic applications has increased exponentially. Many different systems and strategies have been developed for drug targeting to pathol. sites, as well as for visualizing and quantifying important (patho-) physiol. processes. In addn., ever more efforts have been undertaken to combine diagnostic and therapeutic properties within a single nanomedicine formulation. These so-called nanotheranostics are able to provide valuable information on drug delivery, drug release and drug efficacy, and they are considered to be highly useful for personalizing nanomedicine-based (chemo-) therapeutic interventions.
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      The big picture on nanomedicine: the state of investigational and approved nanomedicine products
      Etheridge, Michael L.; Campbell, Stephen A.; Erdman, Arthur G.; Haynes, Christy L.; Wolf, Susan M.; McCullough, Jeffrey
      Nanomedicine (New York, NY, United States) (2013), 9 (1), 1-14CODEN: NANOBF; ISSN:1549-9634. (Elsevier)
      Developments in nanomedicine are expected to provide solns. to many of modern medicine's unsolved problems, so it is no surprise that the literature contains many articles discussing the subject. However, existing reviews tend to focus on specific sectors of nanomedicine or to take a very forward-looking stance and fail to provide a complete perspective on the current landscape. This article provides a more comprehensive and contemporary inventory of nanomedicine products. A keyword search of literature, clin. trial registries, and the Web yielded 247 nanomedicine products that are approved or in various stages of clin. study. Specific information on each was gathered, so the overall field could be described based on various dimensions, including FDA classification, approval status, nanoscale size, treated condition, nanostructure, and others. In addn. to documenting the many nanomedicine products already in use in humans, this study indentifies several interesting trends forecasting the future of nanomedicine.In this one of a kind review, the state of nanomedicine commercialization is discussed, concg. only on nanomedicine-based developments and products that are either in clin. trials or have already been approved for use.
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      Mitra, Amitava; Nan, Anjan; Line, Bruce R.; Ghandehari, Hamidreza
      Current Pharmaceutical Design (2006), 12 (36), 4729-4749CODEN: CPDEFP; ISSN:1381-6128. (Bentham Science Publishers Ltd.)
      A review. Several nanoscale carriers (nanoparticles, liposomes, water-sol. polymers, micelles and dendrimers) have been developed for targeted delivery of cancer diagnostic and therapeutic agents. These carriers can selectively target cancer sites and carry large payloads, thereby improving cancer detection and therapy effectiveness. Further, the combination of newer nuclear imaging techniques providing high sensitivity and spatial resoln. such as dual modality imaging with positron emission tomog./computed tomog. and use of nanoscale devices to carry diagnostic and therapeutic radionuclides with high target specificity can enable more accurate detection, staging and therapy planning of cancer. The successful clin. applications of radiolabeled monoclonal antibodies for cancer detection and therapy bode well for the future of nanoscale carrier systems in clin. oncol. Several radiolabeled multifunctional nanocarriers have been effective in detecting and treating cancer in animal models. Nonetheless, further preclin., clin. and long-term toxicity studies will be required to translate this technol. to the care of patients with cancer. The objective of this review is to present a brief but comprehensive overview of the various nuclear imaging techniques and the use of nanocarriers to deliver radionuclides for the diagnosis and therapy of cancer.
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      Genotoxicity of different nanocarriers: possible modifications for the delivery of nucleic acids
      Shah, Vatsal; Taratula, Oleh; Garbuzenko, Olga B.; Patil, Mahesh L.; Savla, Ronak; Zhang, Min; Minko, Tamara
      Current Drug Discovery Technologies (2013), 10 (1), 8-15CODEN: CDDTAF; ISSN:1570-1638. (Bentham Science Publishers Ltd.)
      The prevention of cyto- and genotoxicity of nanocarriers is an important task in nanomedicine. In the present investigation, we, at the first time using similar exptl. conditions, compared genotoxicity of nanocarriers with different compn., architecture, size, mol. wt. and charge. Poly(ethylene glycol) polymers, neutral and cationic liposomes, micelles, poly(amido amine) and poly(propyleneimine) dendrimers, quantum dots, mesoporous silica, and supermagnetic iron oxide (SPIO) nanoparticles were studied. All nanoparticles were used in non-cytotoxic concns. However, even in these concns., pos. charged cationic liposomes, dendrimers, and SPIO nanoparticles induced genotoxicity leading to the significant formation of micronuclei in cells. Neg. charged and neutral nanocarriers were not genotoxic. A strong pos. correlation was found between the no. of formed micronuclei and the pos. charge of nanocarriers. We proposed modifications of both types of dendrimers and SPIO nanoparticles that substantially decreased their genotoxicity and allowed for an efficient intracellular delivery of nucleic acids.
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      Garbuzenko, O. B.; Saad, M.; Pozharov, V. P.; Reuhl, K. R.; Mainelis, G.; Minko, T. Inhibition of lung tumor growth by complex pulmonary delivery of drugs with oligonucleotides as suppressors of cellular resistance Proc. Natl. Acad. Sci. U. S. A. 2010, 107, 10737– 10742
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      Taratula, O.; Kuzmov, A.; Shah, M.; Garbuzenko, O. B.; Minko, T. Nanostructured lipid carriers as multifunctional nanomedicine platform for pulmonary co-delivery of anticancer drugs and siRNA J. Controlled Release 2013, 171, 349– 357
      11
      Nanostructured lipid carriers as multifunctional nanomedicine platform for pulmonary co-delivery of anticancer drugs and siRNA
      Taratula, Oleh; Kuzmov, Andriy; Shah, Milin; Garbuzenko, Olga B.; Minko, Tamara
      Journal of Controlled Release (2013), 171 (3), 349-357CODEN: JCREEC; ISSN:0168-3659. (Elsevier B.V.)
      We developed, synthesized, and tested a multifunctional nanostructured lipid nanocarrier-based system (NLCS) for efficient delivery of an anticancer drug and siRNA directly into the lungs by inhalation. The system contains: (1) nanostructured lipid carriers (NLC); (2) anticancer drug (doxorubicin or paclitaxel); (3) siRNA targeted to MRP1 mRNA as a suppressor of pump drug resistance; (4) siRNA targeted to BCL2 mRNA as a suppressor of nonpump cellular resistance and (5) a modified synthetic analog of LH-releasing hormone (LHRH) as a targeting moiety specific to the receptors that are overexpressed in the plasma membrane of lung cancer cells. The NLCS was tested in vitro using human lung cancer cells and in vivo utilizing mouse orthotopic model of human lung cancer. After inhalation, the proposed NLCS effectively delivered its payload into lung cancer cells leaving healthy lung tissues intact and also significantly decreasing the exposure of healthy organs when compared with i.v. injection. The NLCS showed enhanced antitumor activity when compared with i.v. treatment. The data obtained demonstrated high efficiency of proposed NLCS for tumor-targeted local delivery by inhalation of anticancer drugs and mixt. of siRNAs specifically to lung cancer cells and, as a result, efficient suppression of tumor growth and prevention of adverse side effects on healthy organs.
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      Mussi, S. V.; Sawant, R.; Perche, F.; Oliveira, M. C.; Azevedo, R. B.; Ferreira, L. A.; Torchilin, V. P. Novel nanostructured lipid carrier co-loaded with doxorubicin and docosahexaenoic acid demonstrates enhanced in vitro activity and overcomes drug resistance in MCF-7/Adr cells Pharm. Res. 2014, 8, 1882– 1892
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      Wang, T.; Hartner, W. C.; Gillespie, J. W.; Praveen, K. P.; Yang, S.; Mei, L. A.; Petrenko, V. A.; Torchilin, V. P. Enhanced tumor delivery and antitumor activity in vivo of liposomal doxorubicin modified with MCF-7-specific phage fusion protein Nanomed.: Nanotechnol., Biol., Med. 2014, 10, 421– 430
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      Tong, S. W.; Xiang, B.; Dong, D. W.; Qi, X. R. Enhanced antitumor efficacy and decreased toxicity by self-associated docetaxel in phospholipid-based micelles Int. J. Pharm. 2012, 434, 413– 419
      14
      Enhanced antitumor efficacy and decreased toxicity by self-associated docetaxel in phospholipid-based micelles
      Tong, Shu-Wen; Xiang, Bai; Dong, Da-Wen; Qi, Xian-Rong
      International Journal of Pharmaceutics (Amsterdam, Netherlands) (2012), 434 (1-2), 413-419CODEN: IJPHDE; ISSN:0378-5173. (Elsevier B.V.)
      To overcome the poor aq. soly. of docetaxel (DTX) and the side effects of the emulsifier in the marketed formulation, we have developed a DTX-loaded micelle using a nontoxic and biodegradable amphiphilic diblock copolymer, methoxy polyethylene glycol-distearoylphosphatidylethanolamine (mPEG2000-DSPE). The prepd. micelles exhibited a core-shell structure, and DTX was successfully encapsulated in the core with an encapsulation efficiency of 97.31 ± 2.95% and a drug loading efficiency of 3.14 ± 0.13%. The micelles were spherical with a hydrodynamic diam. of approx. 20 nm, which could meet the requirement for in vivo administration, and were expected to enhance the drug's antitumor efficacy and to decrease its toxicity. To evaluate the DTX-loaded micelles, we chose a well marketed formulation, Taxotere, as the control. The prepd. DTX micelle had a similar antiproliferative effect to Taxotere in vitro but a significantly better antitumor efficacy than Taxotere in vivo, which may be caused by passive targeting of the tumor by the micelles. In addn., the safety evaluation revealed that the DTX micelle was a qualified drug for use in vivo. Based on the exptl. results, we propose that mPEG2000-DSPE micelle is a potent carrier for DTX.
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    15. 15
      Zhao, B. J.; Ke, X. Y.; Huang, Y.; Chen, X. M.; Zhao, X.; Zhao, B. X.; Lu, W. L.; Lou, J. N.; Zhang, X.; Zhang, Q. The antiangiogenic efficacy of NGR-modified PEG-DSPE micelles containing paclitaxel (NGR-M-PTX) for the treatment of glioma in rats J. Drug Target 2011, 19, 382– 390
      15
      The antiangiogenic efficacy of NGR-modified PEG-DSPE micelles containing paclitaxel (NGR-M-PTX) for the treatment of glioma in rats
      Zhao, Bo-Jun; Ke, Xi-Yu; Huang, Yue; Chen, Xiao-Mei; Zhao, Xin; Zhao, Bing-Xiang; Lu, Wan-liang; Lou, Jin-Ning; Zhang, Xuan; Zhang, Qiang
      Journal of Drug Targeting (2011), 19 (5), 382-390CODEN: JDTAEH; ISSN:1026-7158. (Informa Healthcare)
      Aminopeptidase N (APN), recognized by Asn-Gly-Arg (NGR) peptides, is expressed in the pericytes assocd. with the BBB, and the main objective of this study is to confirm the hypothesis that NGR-modified DSPE-PEG micelles contg. paclitaxel (NGR-M-PTX) can bind to and kill brain tumor angiogenic blood vessels and penetrate into the brain tumor interstitial space, resulting in direct cell death. NGR-M-PTX is prepd. by a thin-film hydration method. The in vitro targeting characteristics of NGR-modified micelles on BMEC (murine brain microvascular endothelial cells) were investigated. The effect of NGR-M-PTX on BMEC proliferation and the cytotoxicity of NGR-M-PTX in C6 glioma cells were also tested. The antitumor activity NGR-M-PTX was evaluated in C6 glioma tumor-bearing rats in vivo. The particle size of NGR-M-PTX was approx. 54.2 nm. The drug encapsulation efficiency of NGR-M-PTX was 82.11 ± 2.82%. The cellular coumarin-6 level of NGR-M-coumarin-6 in the BMEC was about 2.2-fold higher than that of M-coumarin-6. BMEC proliferation was significantly inhibited by NGR-M-PTX. NGR-M-PTX had a much lower IC50 value than M-PTX and free drug. The growth of C6 glioma tumor was markedly inhibited by NGR-M-PTX compared with Taxol. In conclusion, our results show that antiangiogenic therapy using NGR-M-PTX exhibits potent in vivo antitumor activity in a C6 glioma-bearing animal model.
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    16. 16
      Abouzeid, A. H.; Patel, N. R.; Rachman, I. M.; Senn, S.; Torchilin, V. P. Anti-cancer activity of anti-GLUT1 antibody-targeted polymeric micelles co-loaded with curcumin and doxorubicin J. Drug Target 2013, 21, 994– 1000
      16
      Anticancer activity of anti-GLUT1 antibody-targeted polymeric micelles co-loaded with curcumin and doxorubicin
      Abouzeid, Abraham H.; Patel, Niravkumar R.; Rachman, Ilya M.; Senn, Sean; Torchilin, Vladimir P.
      Journal of Drug Targeting (2013), 21 (10), 994-1000CODEN: JDTAEH; ISSN:1026-7158. (Informa Healthcare)
      Background: Treatment of late stage cancers has proven to be a very difficult task. Targeted therapy and combinatory drug administration may be the soln. Purpose: The study was performed to evaluate the therapeutic efficacy of PEG-PE micelles, co-loaded with curcumin (CUR) and doxorubicin (DOX), and targeted with anti-GLUT1 antibody (GLUT1) against HCT-116 human colorectal adenocarcinoma cells both in vitro and in vivo. Methods: HCT-116 cells were treated with non-targeted and GLUT1-targeted CUR and DOX micelles as a single agent or in combination. Cells were inoculated in female nude mice. Established tumors were treated with the micellar formulations at a dose of 4 mg/kg CUR and 0.4 mg/kg DOX every 2 d for a total of 7 injections. Results: CUR + DOX-loaded micelles decorated with GLUT1 had a robust killing effect even at low doses of DOX in vitro. At the doses chosen, non-targeted CUR and CUR + DOX micelles did not exhibit any significant tumor inhibition vs. control. However, GLUT1-CUR and GLUT1-CUR + DOX micelles showed a significant tumor inhibition effect with an improvement in survival. Conclusion: We showed a dramatic improvement in efficacy between the non-targeted and GLUT1-targeted formulations both in vitro and in vivo. Hence, we confirmed that GLUT1-CUR + DOX micelles are effective and deserve further investigation.
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    17. 17
      Sawant, R. R.; Jhaveri, A. M.; Koshkaryev, A.; Qureshi, F.; Torchilin, V. P. The effect of dual ligand-targeted micelles on the delivery and efficacy of poorly soluble drug for cancer therapy J. Drug Target 2013, 21, 630– 638
      17
      The effect of dual ligand-targeted micelles on the delivery and efficacy of poorly soluble drug for cancer therapy
      Sawant, Rupa R.; Jhaveri, Aditi M.; Koshkaryev, Alexander; Qureshi, Farooq; Torchilin, Vladimir P.
      Journal of Drug Targeting (2013), 21 (7), 630-638CODEN: JDTAEH; ISSN:1026-7158. (Informa Healthcare)
      We prepd. and evaluated transferrin (Tf) and monoclonal antibody (mAb) 2C5-modified dual ligand-targeted poly(ethylene glycol)-phosphatidylethanolamine micelles loaded with a poorly sol. drug, R547 (a selective ATP-competitive cyclin-dependent kinase inhibitor) for enhancement of targeting efficiency and cytotoxicity in vitro and in vivo to A2780 ovarian carcinoma compared to single ligand-targeted micelles. Micellar solubilization significantly improved the soly. of R547 from 1 to 800 μg/mL. The size of modified and non-modified micelles was 13-16 nm. Flow cytometry indicated significantly enhanced cellular assocn. of dual ligand-targeted micelles compared to single ligand-targeted micelles. Confocal microscopy confirmed the Tf receptor-mediated endocytosis of rhodamine-labeled Tf-modified micelles after staining the micelle-treated cells with the endosomal marker Tf-Alexa488. The optimized dual-targeted micelles enhanced cytotoxicity in vitro against A2780 ovarian cancer cells compared to plain and single ligand-targeted micelles. Interestingly, in vivo anti-tumor efficacy was more pronounced for the prepn. with a single-targeting ligand (Tf). The specific combination Tf and mAb 2C5 did not yield the expected increase in efficacy as was obsd. in vitro. This observation suggests that the relationships between targeting ligands in vivo could be more complex than in simplified in vitro systems, and the results of the optimization process should always be verified in vivo.
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      Shcharbin, D.; Shakhbazau, A.; Bryszewska, M. Poly(amidoamine) dendrimer complexes as a platform for gene delivery Exp. Opin. Drug Deliv. 2013, 10, 1687– 1698
      There is no corresponding record for this reference.
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      Mignani, S.; El Kazzouli, S.; Bousmina, M.; Majoral, J. P. Expand classical drug administration ways by emerging routes using dendrimer drug delivery systems: a concise overview Adv. Drug Deliv Rev. 2013, 65, 1316– 1330
      There is no corresponding record for this reference.
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      Najlah, M.; D’Emanuele, A. Synthesis of dendrimers and drug-dendrimer conjugates for drug delivery Curr. Opin Drug Discov. Devel. 2007, 10, 756– 767
      20
      Synthesis of dendrimers and drug-dendrimer conjugates for drug delivery
      Najlah, Mohammad; D'Emanuele, Antony
      Current Opinion in Drug Discovery & Development (2007), 10 (6), 756-767CODEN: CODDFF; ISSN:1367-6733. (Thomson Scientific)
      A review. Dendrimers constitute a class of polymers that possess a well-defined structure allowing the precise control of size, shape and terminal group functionality. Their utility has been explored for a wide range of pharmaceutical applications. There is growing interest in the design and synthesis of novel biocompatible dendrimers and a no. of novel dendrimer architectures are discussed in this review. Recently, there has also been interest in the design of drug-dendrimer prodrugs and several of these systems are described, with emphasis on how the properties of such carriers may be tailored via surface engineering.
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    21. 21
      Neerman, M. F.; Zhang, W.; Parrish, A. R.; Simanek, E. E. In vitro and in vivo evaluation of a melamine dendrimer as a vehicle for drug delivery Int. J. Pharm. 2004, 281, 129– 132
      21
      In vitro and in vivo evaluation of a melamine dendrimer as a vehicle for drug delivery
      Neerman, Michael F.; Zhang, Wen; Parrish, Alan R.; Simanek, Eric E.
      International Journal of Pharmaceutics (2004), 281 (1-2), 129-132CODEN: IJPHDE; ISSN:0378-5173. (Elsevier B.V.)
      Cell-based and acute and subchronic in vivo toxicity profiles of a dendrimer based on melamine reveal that this class of mols. warrants addnl. study as vehicles for drug delivery. In cell culture, a substantial decrease in viability was obsd. at 0.1 mg/mL. For the acute studies, mice were administered 2.5, 10, 40 and 160 mg/kg of dendrimer via i.p. injection. At 160 mg/kg, 100% mortality was seen 6-12 h after injection. For the other cohorts, blood chem. work revealed no renal damage was taking place at 48 h. Liver enzyme activity nearly doubled for the mice treated at 40 mg/kg suggesting hepatotoxicity. For the subchronic studies, three i.p. injections of 2.5-40 mg/kg of dendrimers were administered at 3-wk intervals. No mortality was obsd. Forty-eight hours following the last administration, blood chem. revealed no renal damage, but liver damage was indicated by elevated serum enzyme activity at the highest dose. Histopathol. data further confirms that doses up to 10 mg/kg show no hepatic damage at subchronic doses. However, subchronic doses at 40 mg/kg lead to extensive liver necrosis.
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    22. 22
      He, Q.; Shi, J. MSN anti-cancer nanomedicines: Chemotherapy enhancement, overcoming of drug resistance, and metastasis inhibition Adv. Mater. 2014, 26, 391– 411
      22
      MSN Anti-Cancer Nanomedicines: Chemotherapy Enhancement, Overcoming of Drug Resistance, and Metastasis Inhibition
      He, Qianjun; Shi, Jianlin
      Advanced Materials (Weinheim, Germany) (2014), 26 (3), 391-411CODEN: ADVMEW; ISSN:0935-9648. (Wiley-VCH Verlag GmbH & Co. KGaA)
      A review. In the anti-cancer war, there are three main obstacles resulting in high mortality and recurrence rate of cancers: the severe toxic side effect of anti-cancer drugs to normal tissues due to the lack of tumor-selectivity, the multi-drug resistance (MDR) to free chemotherapeutic drugs and the deadly metastases of cancer cells. The development of state-of-art nanomedicines based on mesoporous silica nanoparticle (MSNs) is expected to overcome the above three main obstacles. In the view of the fast development of anti-cancer strategy, this review highlights the most recent advances of MSN anti-cancer nanomedicines in enhancing chemotherapeutic efficacy, overcoming the MDR and inhibiting metastasis. Furthermore, we give an outlook of the future development of MSNs-based anti-cancer nanomedicines, and propose several innovative and forward-looking anti-cancer strategies, including tumor tissue-cell-nuclear successionally targeted drug delivery strategy, tumor cell-selective nuclear-targeted drug delivery strategy, multi-targeting and multi-drug strategy, chemo-/radio-/photodynamic-/ultrasound-/thermo-combined multi-modal therapy by virtue of functionalized hollow/rattle-structured MSNs.
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    23. 23
      Taratula, O.; Garbuzenko, O. B.; Chen, A. M.; Minko, T. Innovative strategy for treatment of lung cancer: targeted nanotechnology-based inhalation co-delivery of anticancer drugs and siRNA J. Drug Target 2011, 19, 900– 914
      23
      Innovative strategy for treatment of lung cancer: targeted nanotechnology-based inhalation co-delivery of anticancer drugs and siRNA
      Taratula, Oleh; Garbuzenko, Olga B.; Chen, Alex M.; Minko, Tamara
      Journal of Drug Targeting (2011), 19 (10), 900-914CODEN: JDTAEH; ISSN:1026-7158. (Informa Healthcare)
      A tumor targeted mesoporous silica nanoparticles (MSN)-based drug delivery system (DDS) was developed for inhalation treatment of lung cancer. The system was capable of effectively delivering inside cancer cells anticancer drugs (doxorubicin and cisplatin) combined with two types of siRNA targeted to MRP1 and BCL2 mRNA for suppression of pump and nonpump cellular resistance in non-small cell lung carcinoma, resp. Targeting of MSN to cancer cells was achieved by the conjugation of LHRH peptide on the surface of MSN via poly(ethylene glycol) spacer. The delivered anticancer drugs and siRNA preserved their specific activity leading to the cell death induction and inhibition of targeted mRNA. Suppression of cellular resistance by siRNA effectively delivered inside cancer cells and substantially enhanced the cytotoxicity of anticancer drugs. Local delivery of MSN by inhalation led to the preferential accumulation of nanoparticles in the mouse lungs, prevented the escape of MSN into the systemic circulation, and limited their accumulation in other organs. The exptl. data confirm that the developed DDS satisfies the major prerequisites for effective treatment of non-small cell lung carcinoma. Therefore, the proposed cancer-targeted MSN-based system for complex delivery of drugs and siRNA has high potential in the effective treatment of lung cancer.
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    24. 24
      Perro, A.; Reculusa, S.; Ravaine, S.; Bourgeat-Lami, E.; Duguet, E. Design and synthesis of Janus micro- and nanoparticles J. Mater. Chem. 2005, 15, 3745– 3760
      24
      Design and synthesis of Janus micro- and nanoparticles
      Perro, Adeline; Reculusa, Stephane; Ravaine, Serge; Bourgeat-Lami, Elodie; Duguet, Etienne
      Journal of Materials Chemistry (2005), 15 (35-36), 3745-3760CODEN: JMACEP; ISSN:0959-9428. (Royal Society of Chemistry)
      A review. Because the Roman god Janus was usually represented with two heads placed back to back, the term Janus is used for the description of particles whose surfaces of both hemispheres are different from a chem. point of view. So, they could be used as building blocks for supraparticular assemblies, as dual-functionalized devices, as particular surfactants if one hemisphere is hydrophilic and the other hydrophobic, etc. If they could allow the segregation of neg. charges on one hemisphere and pos. charges on the other one, they would display a giant dipole moment allowing their remote positioning by rotation in an elec. field as a function of field polarity. This review deals with the great and imaginative efforts which were devoted to the synthesis of Janus particles in the last fifteen years. A special emphasis is made on scalable techniques and on those which apply to the prepn. of Janus particles in the nanometer range. Specific properties and applications of Janus particles are discussed.
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    25. 25
      Romanski, F. S.; Winkler, J. S.; Riccobene, R. C.; Tomassone, M. S. Production and characterization of anisotropic particles from biodegradable materials Langmuir 2012, 28, 3756– 3765
      There is no corresponding record for this reference.
    26. 26
      Yoo, J. W.; Doshi, N.; Mitragotri, S. Adaptive micro and nanoparticles: Temporal control over carrier properties to facilitate drug delivery Adv. Drug Deliv Rev. 2011, 63, 1247– 1256
      There is no corresponding record for this reference.
    27. 27
      Champion, J. A.; Mitragotri, S. Role of target geometry in phagocytosis Proc. Natl. Acad. Sci. U. S. A. 2006, 103, 4930– 4934
      27
      Role of target geometry in phagocytosis
      Champion, Julie A.; Mitragotri, Samir
      Proceedings of the National Academy of Sciences of the United States of America (2006), 103 (13), 4930-4934CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
      Phagocytosis is a principal component of the body's innate immunity in which macrophages internalize targets in an actin-dependent manner. Targets vary widely in shape and size and include particles such as pathogens and senescent cells. Despite considerable progress in understanding this complicated process, the role of target geometry in phagocytosis has remained elusive. Previous studies on phagocytosis have been performed using spherical targets, thereby overlooking the role of particle shape. Using polystyrene particles of various sizes and shapes, we studied phagocytosis by alveolar macrophages. We report a surprising finding that particle shape, not size, plays a dominant role in phagocytosis. All shapes were capable of initiating phagocytosis in at least one orientation. However, the local particle shape, measured by tangent angles, at the point of initial contact dictates whether macrophages initiate phagocytosis or simply spread on particles. The local shape dets. the complexity of the actin structure that must be created to initiate phagocytosis and allow the membrane to move over the particle. Failure to create the required actin structure results in simple spreading and not internalization. Particle size primarily impacts the completion of phagocytosis in cases where particle vol. exceeds the cell vol.
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    28. 28
      Tomasini, M. D.; Zablocki, K.; Petersen, L. K.; Moghe, P. V.; Tomassone, M. S. Coarse grained molecular dynamics of engineered macromolecules for the inhibition of oxidized low-density lipoprotein uptake by macrophage scavenger receptors Biomacromolecules 2013, 14, 2499– 2509
      There is no corresponding record for this reference.
    29. 29
      Mainardes, R. M.; Evangelista, R. C. PLGA nanoparticles containing praziquantel: Effect of formulation variables on size distribution Int. J. Pharm. 2005, 290, 137– 144
      29
      PLGA nanoparticles containing praziquantel: effect of formulation variables on size distribution
      Mainardes, Rubiana M.; Evangelista, Raul C.
      International Journal of Pharmaceutics (2005), 290 (1-2), 137-144CODEN: IJPHDE; ISSN:0378-5173. (Elsevier B.V.)
      Praziquantel has been shown to be highly effective against all known species of Schistosoma infecting humans. Spherical nanoparticulate drug carriers made of poly(D,L-lactide-co-glycolide) acid with controlled size were designed. Praziquantel, a hydrophobic mol., was entrapped into the nanoparticles with theor. loading varying from 10 to 30% (wt./wt.). This study investigates the effects of some process variables on the size distribution of nanoparticles prepd. by emulsion-solvent evapn. method. The results show that sonication time, PLGA and drug amts., PVA concn., ratio between aq. and org. phases, and the method of solvent evapn. have a significant influence on size distribution of the nanoparticles.
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    30. 30
      Niwa, T.; Takeuchi, H.; Hino, T.; Kunou, N.; Kawashima, Y. In vitro drug release behavior of D,L-lactide/glycolide copolymer (PLGA) nanospheres with nafarelin acetate prepared by a novel spontaneous emulsification solvent diffusion method J. Pharm. Sci. 1994, 83, 727– 732
      There is no corresponding record for this reference.
    31. 31
      Ubrich, N.; Bouillot, P.; Pellerin, C.; Hoffman, M.; Maincent, P. Preparation and characterization of propranolol hydrochloride nanoparticles: A comparative study J. Controlled Release 2004, 97, 291– 300
      31
      Preparation and characterization of propranolol hydrochloride nanoparticles: a comparative study
      Ubrich, Nathalie; Bouillot, Philippe; Pellerin, Christina; Hoffman, Maurice; Maincent, Philippe
      Journal of Controlled Release (2004), 97 (2), 291-300CODEN: JCREEC; ISSN:0168-3659. (Elsevier)
      The water-in-oil-in-water (w/o/w) emulsification process is the method of choice for the encapsulation inside polymeric particles of hydrophilic drugs such as proteins and peptides which are high mol. wt. macromols. Our objective was to apply this technique in order to formulate nanoparticles loaded with both a hydrophilic and a low mol. wt. drug such as propranolol-HCl. Nanoparticles were prepd. using a pressure homogenization device with various polymers (poly-ε-caprolactone, poly(lactide-co-glycolide), ethylcellulose) and different amts. of drug and were compared in terms of particle size, encapsulation efficiency and drug release. Higher encapsulation efficiencies were obtained with both PCL (77.3%) and PLGA (83.3%) compared to ethylcellulose (66.8%). The in vitro drug release was characterized by an initial burst and an incomplete dissoln. of the drug. When decreasing the polymer/drug ratio, the release appeared more controlled and prolonged up to 8 h. It can be concluded that nanoparticles prepd. by w/o/w emulsification followed by solvent evapn. might be potential drug carriers for low mol. wt. and hydrophilic drugs.
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    32. 32
      Convention, U. S. P.USP 30; United States Pharmacopeial Convention , 2006.
      There is no corresponding record for this reference.
    33. 33
      Basu, S.; Harfouche, R.; Soni, S.; Chimote, G.; Mashelkar, R. A.; Sengupta, S. Nanoparticle-mediated targeting of MAPK signaling predisposes tumor to chemotherapy Proc. Natl. Acad. Sci. U. S. A. 2009, 106, 7957– 7961
      There is no corresponding record for this reference.
    34. 34
      Mainelis, G.; Seshadri, S.; Garbuzenko, O. B.; Han, T.; Wang, Z.; Minko, T. Characterization and application of a nose-only exposure chamber for inhalation delivery of liposomal drugs and nucleic acids to mice J. Aerosol Med. Pulm. Drug Deliv. 2013, 26, 345– 354
      34
      Characterization and Application of a Nose-Only Exposure Chamber for Inhalation Delivery of Liposomal Drugs and Nucleic Acids to Mice
      Mainelis, G.; Seshadri, S.; Garbuzenko, O. B.; Han, T.; Wang, Z.; Minko, T.
      Journal of Aerosol Medicine and Pulmonary Drug Delivery (2013), 26 (6), 345-354CODEN: JAMPC4; ISSN:1941-2711. (Mary Ann Liebert, Inc.)
      Background: A small nose-only exposure chamber was evaluated for inhalation delivery of drug carrier systems (DCSs) to mice for the treatment of lung cancer. The chamber then was used for inhalation delivery of an anticancer drug, antisense oligonucleotides (ASO), and small interfering RNA (siRNA) directly to the cancerous lungs of mice. Methods: The uniformity of particle delivery across the ports of the exposure chamber and stability of the DCS (liposomes) during continuous aerosolization by a Collison nebulizer were examd. The mean produced particle size by no. was approx. 130 nm, and the mass median diam. was approx. 270 nm. The system was then used to deliver DCS contg. doxorubicin (DOX) and ASO or siRNA targeted to multidrug resistance-assocd. protein 1 (MRP1) mRNA as suppressors of cancer cell resistance. The retention of the drug in the lungs and the effect on tumor size were compared after inhalation delivery and i.v. injection in a nu/nu mouse model of lung cancer. Results: The aerosol mass across the four inhalation ports had a coeff. of variation of less than 12%, and approx. 1.4% of the nebulized mass was available for inhalation at each port. The mean size of 130 nm of liposomal DCS did not change significantly during continuous 60-min aerosolization. For inhalation delivery of DCS with DOX+ASO/siRNA, the amt. of drugs available for inhalation was lower compared with i.v. injection of DOX; however, the obsd. lung dose and the retention time were significantly higher. The delivery of DOX+ASO/siRNA via inhalation resulted in tumor vol. redn. of more than 90%, whereas only about 40% redn. was achieved after i.v. injection of DOX. Conclusions: The investigated exposure system is suitable for inhalation delivery of complex DCS, and its use to deliver DCS contg. anticancer drugs and resistance suppressors via inhalation offered a superior method for lung cancer treatment in mice compared with i.v. injections.
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    35. 35
      Kumari, A.; Yadav, S. K.; Yadav, S. C. Biodegradable polymeric nanoparticles based drug delivery systems Colloids Surf., B 2010, 75, 1– 18
      35
      Biodegradable polymeric nanoparticles based drug delivery systems
      Kumari, Avnesh; Yadav, Sudesh Kumar; Yadav, Subhash C.
      Colloids and Surfaces, B: Biointerfaces (2010), 75 (1), 1-18CODEN: CSBBEQ; ISSN:0927-7765. (Elsevier B.V.)
      A review. Biodegradable nanoparticles were used frequently as drug delivery vehicles due to its grand bioavailability, better encapsulation, control release and less toxic properties. Various nanoparticulate systems, general synthesis and encapsulation process, control release and improvement of therapeutic value of nanoencapsulated drugs are covered in this review. The authors have highlighted the impact of nanoencapsulation of various disease related drugs on biodegradable nanoparticles such as PLGA, PLA, chitosan, gelatin, polycaprolactone and poly-alkyl-cyanoacrylates.
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    36. 36
      Makadia, H. K.; Siegel, S. J. Poly Lactic-co-glycolic acid (PLGA) as biodegradable controlled drug delivery carrier Polymers 2011, 3, 1377– 1397
      36
      Poly lactic-co-glycolic acid (PLGA) as biodegradable controlled drug delivery carrier
      Makadia, Hirenkumar K.; Siegel, Steven J.
      Polymers (Basel, Switzerland) (2011), 3 (3), 1377-1397CODEN: POLYCK; ISSN:2073-4360. (MDPI AG)
      A review. In past two decades poly lactic-co-glycolic acid (PLGA) has been among the most attractive polymeric candidates used to fabricate devices for drug delivery and tissue engineering applications. PLGA is biocompatible and biodegradable, exhibits a wide range of erosion times, has tunable mech. properties and most importantly, is a FDA approved polymer. In particular, PLGA has been extensively studied for the development of devices for controlled delivery of small mol. drugs, proteins and other macromols. in com. use and in research. This manuscript describes the various fabrication techniques for these devices and the factors affecting their degrdn. and drug release.
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    37. 37
      Sonaje, K.; Italia, J. L.; Sharma, G.; Bhardwaj, V.; Tikoo, K.; Kumar, M. N. V. R. Development of biodegradable nanoparticles for oral delivery of ellagic acid and evaluation of their antioxidant efficacy against cyclosporine A-induced nephrotoxicity in rats Pharm. Res. 2007, 24, 899– 908
      There is no corresponding record for this reference.
    38. 38
      Gao, Z. H.; Crowley, W. R.; Shukla, A. J.; Johnson, J. R.; Reger, J. F. Controlled release of contraceptive steroids from biodegradable and injectable gel formulations: in vivo evaluation Pharm. Res. 1995, 12, 864– 868
      There is no corresponding record for this reference.
    39. 39
      Sahoo, S. K.; Panyam, J.; Prabha, S.; Labhasetwar, V. Residual polyvinyl alcohol associated with poly (d,l-lactide-co-glycolide) nanoparticles affects their physical properties and cellular uptake J. Controlled Release 2002, 82, 105– 114
      39
      Residual polyvinyl alcohol associated with poly (D,L-lactide-co-glycolide) nanoparticles affects their physical properties and cellular uptake
      Sahoo, Sanjeeb K.; Panyam, Jayanth; Prabha, Swayam; Labhasetwar, Vinod
      Journal of Controlled Release (2002), 82 (1), 105-114CODEN: JCREEC; ISSN:0168-3659. (Elsevier Science Ltd.)
      Polyvinyl alc. (PVA) is the most commonly used emulsifier in the formulation of poly lactide and poly(D,L-lactide-co-glycolide) (PLGA) polymeric nanoparticles. A fraction of PVA remains assocd. with the nanoparticles despite repeated washing because PVA forms an interconnected network with the polymer at the interface. The objective of this study was to det. the parameters that influence the amt. of residual PVA assocd. with PLGA nanoparticles and its effect on the phys. properties and cellular uptake of nanoparticles. Nanoparticles were formulated by a multiple emulsion-solvent evapn. technique using bovine serum albumin (BSA) as a model protein. The parameters that affected the amt. of residual PVA include the concn. of PVA and the type of org. solvent used in the emulsion. The residual PVA, in turn, influenced different pharmaceutical properties of nanoparticles such as particle size, zeta potential, polydispersity index, surface hydrophobicity, protein loading and also slightly influenced the in vitro release of the encapsulated protein. Importantly, nanoparticles with higher amt. of residual PVA had relatively lower cellular uptake despite their smaller particle size. It is proposed that the lower intracellular uptake of nanoparticles with higher amt. of residual PVA could be related to the higher hydrophilicity of the nanoparticle surface. In conclusion, the residual PVA assocd. with nanoparticles is an important formulation parameter that can be used to modulate the pharmaceutical properties of PLGA nanoparticles.
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    40. 40
      Chong, S. F.; Smith, A. A.; Zelikin, A. N. Microstructured, functional PVA hydrogels through bioconjugation with oligopeptides under physiological conditions Small 2013, 9, 942– 950
      There is no corresponding record for this reference.
    41. 41
      Matsumura, S.; Toshima, K. biodegradation of poly(vinyl alcohol) and vinyl alcohol block as biodegradable segment. In Hydrogels and Biodegradable Polymers for Bioapplications; American Chemical Society: Washington, D.C., 1996; Vol. 627, pp 137– 148.
      There is no corresponding record for this reference.
    42. 42
      Manousaki, E.; Psillakis, E.; Kalogerakis, N.; Mantzavinos, D. Degradation of sodium dodecylbenzene sulfonate in water by ultrasonic irradiation Water Res. 2004, 38, 3751– 3759
      There is no corresponding record for this reference.
    43. 43
      Minko, T. Drug delivery systems. In Martin’s Physical Pharmacy and Pharmaceutical Sciences, 5ed.; Sinko, P., Ed.; Lippincott Williams and Wilkins: New York, 2006; pp 629– 680.
      There is no corresponding record for this reference.
    44. 44
      Garbuzenko, O. B.; Mainelis, G.; Taratula, O.; Minko, T. Inhalation treatment of lung cancer: The influence of composition, size and shape of nanocarriers on their lung accumulation and retention Cancer Biol. Med. 2014, 11, 44– 55
      44
      Inhalation treatment of lung cancer: the influence of composition, size and shape of nanocarriers on their lung accumulation and retention
      Garbuzenko, Olga B.; Mainelis, Gediminas; Taratula, Oleh; Minko, Tamara
      Cancer Biology & Medicine (2014), 11 (1), 44-55CODEN: CBMADQ; ISSN:2095-3941. (Tianjin Medical University Cancer Institute and Hospital)
      Objective: Various nanoparticles have been designed and tested in order to select optimal carriers for the inhalation delivery of anticancer drugs to the lungs. Methods: The following nanocarriers were studied: micelles, liposomes, mesoporous silica nanoparticles (MSNs), poly propyleneimine (PPI) dendrimer-siRNA complexes nanoparticles, quantum dots (QDs), and poly (ethylene glycol) polymers. All particles were characterized using the following methods: dynamic light scattering, zeta potential, at. force microscopy, in vitro cyto- and genotoxicity. In vivo organ distribution of all nanoparticles, retention in the lungs, and anticancer effects of liposomes loaded with doxorubicin were examd. in nude mice after the pulmonary or i.v. delivery. Results: Significant differences in lung uptake were found after the inhalation delivery of lipid-based and non-lipid-based nanoparticles. The accumulation of liposomes and micelles in lungs remained relatively high even 24 h after inhalation when compared with MSNs, QDs, and PPI dendrimers. There were notable differences between nanoparticle accumulation in the lungs and other organs 1 and 3 h after inhalation or i.v. administrations, but 24 h after i.v. injection all nanoparticles were mainly accumulated in the liver, kidneys, and spleen. Inhalation delivery of doxorubicin by liposomes significantly enhanced its anticancer effect and prevented severe adverse side effects of the treatment in mice bearing the orthotopic model of lung cancer. Conclusion: The results of the study demonstrate that lipid-based nanocarriers had considerably higher accumulation and longer retention time in the lungs when compared with non-lipid-based carriers after the inhalation delivery. These particles are most suitable for effective inhalation treatment of lung cancer.
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    45. 45
      Garbuzenko, O. B.; Saad, M.; Betigeri, S.; Zhang, M.; Vetcher, A. A.; Soldatenkov, V. A.; Reimer, D. C.; Pozharov, V. P.; Minko, T. Intratracheal versus intravenous liposomal delivery of siRNA, antisense oligonucleotides and anticancer drug Pharm. Res. 2009, 26, 382– 394
      There is no corresponding record for this reference.
    46. 46
      Ivanova, V.; Garbuzenko, O. B.; Reuhl, K. R.; Reimer, D. C.; Pozharov, V. P.; Minko, T. Inhalation treatment of pulmonary fibrosis by liposomal prostaglandin E2 Eur. J. Pharm. Biopharm 2013, 84, 335– 344
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      Inhalation treatment of pulmonary fibrosis by liposomal prostaglandin E2
      Ivanova, Vera; Garbuzenko, Olga B.; Reuhl, Kenneth R.; Reimer, David C.; Pozharov, Vitaly P.; Minko, Tamara
      European Journal of Pharmaceutics and Biopharmaceutics (2013), 84 (2), 335-344CODEN: EJPBEL; ISSN:0939-6411. (Elsevier B.V.)
      Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and often fatal form of interstitial lung disease. We hypothesized that the local pulmonary delivery of prostaglandin E2 (PGE2) by liposomes can be used for the effective treatment of IPF. To test this hypothesis, we used a murine model of bleomycin-induced IPF to evaluate liposomal delivery of PGE2 topically to the lungs. Animal survival, body wt., hydroxyproline content in the lungs, lung histol., mRNA, and protein expression were studied. After inhalation delivery, liposomes accumulated predominately in the lungs. In contrast, i.v. administration led to the accumulation of liposomes mainly in kidney, liver, and spleen. Liposomal PGE2 prevented the disturbances in the expression of many genes assocd. with the development of IPF, substantially restricted inflammation and fibrotic injury in the lung tissues, prevented decrease in body wt., limited hydroxyproline accumulation in the lungs, and virtually eliminated mortality of animals after intratracheal instillation of bleomycin. In summary, our data provide evidence that pulmonary fibrosis can be effectively treated by the inhalation administration of liposomal form of PGE2 into the lungs. The results of the present investigations make the liposomal form of PGE2 an attractive drug for the effective inhalation treatment of idiopathic pulmonary fibrosis.
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