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Targeted Polymeric Micelle System for Delivery of Combretastatin A4 to Tumor Vasculature In Vitro

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ABSTRACT

Purpose

To develop an efficient tumor vasculature-targeted polymeric micelle delivery system for combretastatin A4 (CA4), a novel antivascular agent.

Methods

CA4-loaded micelles were prepared from poly (ethylene glycol)-b-poly (d, l-lactide) copolymers. RGD peptides that target integrins αvβ3 and αvβ5, markers of angiogenic endothelial cells, were coupled to the surface of micelles. The micelles were characterized in terms of particle size, morphology, drug loading, and drug release. Cellular uptake of micelles was evaluated by fluorometric determination and confocal microscopy. Anti-proliferation of targeted micelles was also evaluated by SRB method.

Results

The mean diameters of CA4-loaded targeted micelles were 25.9 ± 1.3 nm and spherical in shape. Approximately 4 mg/mL of micellar CA4 loading was obtained with an entrapment efficiency of 97.2 ± 1.4%. In vitro release studies revealed that targeted micelles release CA4 in a sustained-release manner within 48 h. In vitro cellular uptake studies demonstrated that targeted micelles significantly facilitated the intracellular delivery of the encapsulated agents via integrin-mediated endocytosis. Anti-proliferation studies showed that targeted micelles containing CA4 present superior efficacy over nontargeted micelles.

Conclusion

These results suggested that RGD conjugated PEG-PLA micelles loading CA4 have potential as a new formulation for targeting angiogenic tumor vasculature.

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ACKNOWLEDGMENTS

The National Basic Research Program of China (973 Program, 2009CB930300), the National Natural Science Foundation of China (30772666), the National High-tech R&D Program (863 Program, 2007AA021811) and the projects from the Ministry of Education are gratefully acknowledged for financial support.

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Authors and Affiliations

  1. State Key Laboratory of Natural and Biomimetic Drugs School of Pharmaceutical Sciences, Peking University, 38 Xueyuan Road, Beijing, 100083, China

    Yiguang Wang, Tingyuan Yang, Xun Wang, Jiancheng Wang, Xuan Zhang & Qiang Zhang

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  1. Yiguang Wang
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  2. Tingyuan Yang
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  3. Xun Wang
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  4. Jiancheng Wang
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  5. Xuan Zhang
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  6. Qiang Zhang
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Corresponding author

Correspondence to Qiang Zhang.

Additional information

Yiguang Wang and Tingyuan Yang contributed equally to this work.

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Wang, Y., Yang, T., Wang, X. et al. Targeted Polymeric Micelle System for Delivery of Combretastatin A4 to Tumor Vasculature In Vitro . Pharm Res 27, 1861–1868 (2010). https://doi.org/10.1007/s11095-010-0184-9

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  • DOI: https://doi.org/10.1007/s11095-010-0184-9

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