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Doxorubicin Loaded pH-sensitive Micelle: Antitumoral Efficacy against Ovarian A2780/DOXR Tumor

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Abstract

Purpose

To evaluate pH-sensitive mixed micelles for multidrug resistant (MDR) ovarian tumor targeting and optical imaging of solid tumors.

Method

Doxorubicin (DOX) encapsulated pH-sensitive mixed micelles composed of poly(l-histidine)(MW 5K)-b-PEG(MW 2K) and poly(l-lactic acid)(3K)-b-PEG (2K)-folate (PHSM-f) were prepared. Folate receptor-mediated endocytosis, drug uptake, endosomal disruption and cell viability were investigated at the cellular level. For in vivo tumor growth inhibition tests, multidrug resistant ovarian A2780/DOXR xenografted nude mice were used. Optical imaging was performed by using a Cy5.5 fluorescence dye-labeled mixed micelle system. Cy5.5 fluorescence intensity at the tumor site was measured in KB epidermoid xenografted nude mice.

Results

In vitro cell viability and drug distribution in the cytoplasm demonstrated the significantly superior efficacy of PHSM-f to free DOX and a control sample of DOX loaded pH-insensitive micelle composed of poly(l-lactic acid)(3K)-b-PEG(2K)/poly(l-lactic acid)(3K)-b-PEG(2K)-folate (80/20 wt/wt%) (PHIM-f). The mechanisms of these results were proved by folate receptor mediated endocytosis of micelle and endosomal disruption function by it. In addition, the optical imaging demonstrated the future application of the diagnositic area. PHSM-f inhibited the growth of multidrug resistant ovarian tumors efficiently in mice, with minimum weight loss.

Conclusions

The pH-sensitive mixed micelle system demonstrates effective antitumor efficacy against the multidrug resistant ovarian tumor A2780/DOXR.

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Acknowledgment

This work was partially supported by NIH CA 101850. Drs. Zhonggao Gao, Kyung Taek Oh, and Han Chang Kang are acknowledged for their help with various experiments.

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Authors and Affiliations

  1. Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, 421 Wakara Way, Suite 318, Salt Lake City, Utah, 84108, USA

    Dongin Kim, Eun Seong Lee & You Han Bae

  2. Biomedical Research Center, Korea Institute of Science and Technology, 39-1 Hawolgok-dong, Seongbuk-gu, Seoul, 136-791, South Korea

    Kyeongsoon Park & Ick Chan Kwon

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  1. Dongin Kim
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  2. Eun Seong Lee
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Correspondence to You Han Bae.

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Kim, D., Lee, E.S., Park, K. et al. Doxorubicin Loaded pH-sensitive Micelle: Antitumoral Efficacy against Ovarian A2780/DOXR Tumor. Pharm Res 25, 2074–2082 (2008). https://doi.org/10.1007/s11095-008-9603-6

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  • DOI: https://doi.org/10.1007/s11095-008-9603-6

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