Shrapnel nanoparticles loading docetaxel inhibit metastasis and growth of breast cancer.

Pengfei Xu, Qingshuo Meng, Huiping Sun, Qi Yin, Haijun Yu, Zhiwen Zhang, Mi Cao, Yingyi Zhang, Yaping Li

Index: Biomaterials 64 , 10-20, (2015)

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Abstract

Metastasis is one of the major obstacles for the successful therapy of breast cancer. To inhibit the metastasis and growth of breast cancer simultaneously, a new docetaxel (DTX) loaded shrapnel nano delivery system with the reduction- and enzyme-sensitive properties was designed and developed. Firstly, methoxy polyethylene glycol-peptide-vitamin E succinate (PPV), a matrix metalloproteinases (MMPs)-sensitive copolymer, was synthesized by conjugating mPEG and vitamin E succinate (VES) using an enzyme-sensitive peptide. Then, DTX loaded methoxy polyethylene glycol-s-s-vitamin E succinate (PSV) micelles (DPM) @ PPV-based liposomes (DPM@PL) were prepared by the incorporation of DPM into the PPV-based liposomes. DPM@PL showed a shrapnel structure with average particle size 113.3 ± 2.7 nm. The drug loading and encapsulation efficiency of DPM@PL were 1.93% and 99.02%, respectively. An obvious burst release (>90%) of drug was observed in the simulated tumor microenvironment with MMPs and reductive glutathione. The cellular uptake and cytotoxicity of DPM@PL in 4T1 cells were significantly enhanced after the pre-treatment of activated MMP-9. Compared with Taxotere(®), DPM@PL remarkably increased the distribution of DTX in lung and tumor of 4T1 tumor-bearing mice, and inhibited the in situ tumor growth and pulmonary metastasis formation effectively through the enhanced DTX-induced apoptosis and the reduced metastasis-promoting proteins expression. Compared with saline group, the inhibitory rates of DPM@PL against tumor volume and lung metastasis were about 81% and 92%, respectively, and it didn't produce the significant systemic toxicity. As a result, DPM@PL could be a promising nano delivery system for the successful therapy of breast cancer.Copyright © 2015 Elsevier Ltd. All rights reserved.