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Matrix Metalloproteinase-Responsive Multifunctional Peptide-Linked Amphiphilic Block Copolymers for Intelligent Systemic Anticancer Drug Delivery.

Authors
  • Ke, Wendong1
  • Zha, Zengshi1
  • Mukerabigwi, Jean Felix1
  • Chen, Weijian1
  • Wang, Yuheng1
  • He, Chuanxin2
  • Ge, Zhishen1
  • 1 CAS Key Laboratory of Soft Matter Chemistry, Department of Polymer Science and Engineering, University of Science and Technology of China , Hefei 230026, Anhui, China. , (China)
  • 2 College of Chemistry and Environmental Engineering, Shenzhen University , Shenzhen 518060, Guangdong, China. , (China)
Type
Published Article
Journal
Bioconjugate Chemistry
Publisher
American Chemical Society
Publication Date
Aug 16, 2017
Volume
28
Issue
8
Pages
2190–2198
Identifiers
DOI: 10.1021/acs.bioconjchem.7b00330
PMID: 28661654
Source
Medline
License
Unknown

Abstract

The amphiphilic block copolymer anticancer drug nanocarriers clinically used or in the progress of clinical trials frequently suffer from modest final therapeutic efficacy due to a lack of intelligent features. For example, the biodegradable amphiphilic block copolymer, poly(ethylene glycol)-b-poly(d,l-lactide) (PEG-PDLLA) has been approved for clinical applications as a paclitaxel (PTX) nanocarrier (Genexol-PM) due to the optimized pharmacokinetics and biodistribution; however, a lack of intelligent features limits the intracellular delivery in tumor tissue. To endow the mediocre polymer with smart properties via a safe and facile method, we introduced a matrix metalloproteinase (MMP)-responsive peptide GPLGVRGDG into the block copolymer via efficient click chemistry and ring-opening polymerization to prepare PEG-GPLGVRGDG-PDLLA (P1). P1 was further self-assembled into micellar nanoparticles (NPs) to load PTX, which show MMP-2-triggered dePEGylation due to cleavage of the peptide linkage. Moreover, the residual VRGDG sequences are retained on the surface of the NPs after dePEGylation, which can serve as ligands to facilitate the cellular uptake. The cytotoxicity of PTX loaded in P1 NPs against 4T1 cells is significantly enhanced as compared with free PTX or PTX-loaded PEG-GPLGVRG-PDLLA (P2) and PEG-PDLLA (P3) NPs. In vivo studies confirmed that PTX-loaded P1 NPs show prolonged blood circulation, which are similar to P2 and P3 NPs but exhibit more-efficient accumulation in the tumor site. Ultimately, PTX-loaded P1 NPs display statistically significant improvement of antitumor activity against tumor-bearing mice via systemic administration. Therefore, the strategy by facile incorporation of a responsive peptide linkage between PEG and PDLLA is a promising approach to improving the therapeutic efficacy of anticancer-drug-loaded amphiphilic block copolymer micelles.

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