title: Shrapnel nanoparticles loading docetaxel inhibit metastasis and growth of breast cancer.
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.
authors.affiliation: State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Pengfei
authors.initials: P
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Qingshuo
authors.initials: Q
authors.lastname: Meng
authors.affiliation: State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China.
authors.forename: Huiping
authors.initials: H
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: yinqi0607@126.com.
authors.forename: Qi
authors.initials: Q
authors.lastname: Yin
authors.affiliation: State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Haijun
authors.initials: H
authors.lastname: Yu
authors.affiliation: State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Zhiwen
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: National Center for Protein Science (Shanghai), Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 201210, China.
authors.forename: Mi
authors.initials: M
authors.lastname: Cao
authors.affiliation: National Center for Protein Science (Shanghai), Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 201210, China.
authors.forename: Yingyi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: ypli@simm.ac.cn.
authors.forename: Yaping
authors.initials: Y
authors.lastname: Li
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D000077143:Docetaxel; D004337:Drug Carriers / Q000008:administration & dosage; D004339:Drug Compounding; D004354:Drug Screening Assays, Antitumor; D005260:Female; D008081:Liposomes / Q000008:administration & dosage; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary*; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008823:Micelles; D015394:Molecular Structure; D053758:Nanoparticles / Q000008:administration & dosage* / Q000627:therapeutic use / Q000633:toxicity; D009363:Neoplasm Proteins / Q000096:biosynthesis; D010316:Particle Size; D010713:Phosphatidylcholines; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000138:chemical synthesis; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D043823:Taxoids / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000633:toxicity; D014018:Tissue Distribution; D024505:Tocopherols / Q000008:administration & dosage* / Q000138:chemical synthesis; D059016:Tumor Microenvironment
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004337:Drug Carriers; D008081:Liposomes; D008823:Micelles; D009363:Neoplasm Proteins; D010713:Phosphatidylcholines; D043823:Taxoids; D000077143:Docetaxel; D011092:Polyethylene Glycols; D024505:Tocopherols
keywords: Breast cancer; Enzyme-sensitive; Metastasis; Nanoparticles; Reduction-sensitive; Shrapnel