Research Article
Liposome formulation of co-encapsulated vincristine and quercetin enhanced antitumor activity in a trastuzumab-insensitive breast tumor xenograft model

https://doi.org/10.1016/j.nano.2011.02.001 Get rights and content

Abstract

Hormone- and trastuzumab-insensitive breast cancer has limited and ineffective clinical treatment options. This study sought to develop a liposome formulation containing a synergistic combination of vincristine and quercetin, with prolonged drug circulation times and coordinated drug release in vivo, to develop effective treatments against this subtype of breast cancer. The 2:1 molar ratio of vincristine/quercetin showed strong synergism in the hormone- and trastuzumab-insensitive JIMT-1 cells. Liposome co-encapsulation prolonged plasma circulation of the two drugs and maintained the synergistic drug ratio in vivo. Furthermore, the co-encapsulated liposome formulation demonstrated the most effective tumor growth inhibition in the JIMT-1 human breast tumor xenograft in comparison with vehicle control, free quercetin, free vincristine and free vincristine/quercetin combinations. Specifically, only the co-encapsulated liposome formulation exhibited significant antitumor activity at two-thirds of the maximum tolerated dose of vincristine, without significant body weight loss in the animals.

From the Clinical Editor

In this study, a novel liposome formulation containing a synergistic combination of vincristine and quercetin was utilized in the treatment of breast cancer. Prolonged drug circulation times and coordinated drug release characterize this effective treatment, which may find its way to clinical applications in the near future.

Graphical Abstract

In vivo antitumor effects of various treatment groups against JIMT-1 xenografts.

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Section snippets

Materials

All lipids were obtained from Avanti Polar Lipids (Alabaster, Alabama). JIMT-1 cells were obtained from Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (Braunschweig, Germany). The materials 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT), dimethylsulfoxide (DMSO) and chloroform were purchased from MP Biomedicals Asia Pacific Pte Ltd (Singapore). Balb/c mice were supplied via the Centre for Animal Resources, National University of Singapore (Singapore), and SCID

In vitro combination effects of free vincristine and quercetin

Previously, we showed that the most synergistic molar ratio of vincristine and quercetin was 2:1 in MDA-MB-231 cells.15 Given that it is important to demonstrate consistent display of synergy across different cell lines for a specific ratio of chemotherapeutic agents,24 it was our aim to assess if a similar trend could be observed in JIMT-1 cells. The in vitro combination effects of vincristine and quercetin were compared among the molar drug ratios of 4:1, 2:1, 1:1 and 1:2. Figure 1 shows the

Discussion

We will discuss our work from the formulation and clinical perspectives. From the formulation perspective, we have demonstrated that the administration of free drug combination in the absence of a drug carrier led to antagonistic CI values in vivo. This highlights the need for a delivery vehicle to attain optimal antitumor efficacy for the vincristine/quercetin combination. Liposomal co-encapsulation of vincristine and quercetin maintained the optimal synergistic drug ratio in plasma to be

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    This work was supported by the Singapore Ministry of Education via the National University of Singapore Academic Research Fund (grant # R-148-050-077-101 & R-148-050-077-133). Man-Yi Wong is a recipient of a research scholarship from Singapore Ministry of Education.

    There are no conflicts of interest in connection with this article.

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