A Novel Combined Micellar System of Lapatinib and Paclitaxel with Enhanced Antineoplastic Effect Against Human Epidermal Growth Factor Receptor-2 Positive Breast Tumor In Vitro

作者：Wei Yan; Xu Shuai; Wang Feng; Zou Aifeng; Zhang Shuang; Xiong Yan; Cao Shilei; Zhang Qizhi; Wang Yajie; Jiang Xinguo^*

来源：Journal of Pharmaceutical Sciences, 2015, 104(1): 165-177.

DOI：10.1002/jps.24234

• lapatinib
• paclitaxel
• poorly water-soluble drugs
• solubility
• micelle
• cancer chemotherapy
• sensitize
• human epidermal growth factor receptor-2
• polymeric drug delivery systems
• conjugation

Lapatinib (LPT) could sensitize human epidermal growth factor receptor-2 (HER-2) positive breast cancer to paclitaxel (PTX) and induce synergetic action with PTX in preclinical test and phase II/III trial. In this study, LPT-conjugated poly (ethylene glycol) (PEG) and poly (lactic acid) (PLA) (LPT-PEG-PLA) was first synthesized and confirmed with H-1 Nuclear Magnetic Resonance and Matrix-Assisted Laser Desorption/ Ionization Time of Flight Mass Spectrometry, which was used for the preparation of a novel PEG-PLA combined micelles of LPT and PTX (PPM-LP). The obtained PPM-LP exhibited uniform, spherical shape with a size of 25.80 +/- 0.47 nm and zeta potential of -3.17 +/- 0.15 mv. PTX existed in molecular or amorphous forms in the micelles and superficial LPT could better delay PTX release. The cytotoxicity of PPM-LP with LPT conjugation against SKBr-3 cells (HER-2 positive) was found to be significantly increasing as compared with PPM-PTX, whereas there was no significant difference against MDA-MB-231 cells (HER-2 negative). PPM-LP could escape from endosomes and be distributed into cytoplasm and led to cell arrest in G2/M and G1/S phases simultaneously. Results of nucleus staining and flow cytometry confirmed that LPT could remarkably increase antineoplastic effect of PTX against SKBr-3 cells. All these results demonstrated that PPM-LP may be a promising drug delivery system for HER-2 positive breast cancer.

• 出版日期2015-1
• 单位中国人民解放军第二军医大学; 复旦大学; 上海医药工业研究院