Dimeric camptothecin-loaded RGD-modified targeted cationic polypeptide-based micelles with high drug loading capacity and redox-responsive drug release capability. (9th November 2017)

• Record Type: Journal Article
• Authors: Guo, Zhaopei; Zhou, Xingzhi; Xu, Mengze; Tian, Huayu; Chen, Xuesi; Chen, Meiwan
• Is Part Of: Biomaterials science. Volume 5:Number 12(2017:Dec.)
• Page Start: 2501
• Page End: 2510
• Publication Date: 2017-11-09
• Subjects: Biomedical materials -- Periodicals; 610.28
• DOI: 10.1039/c7bm00791d
• Languages: English
• ISSNs: 2047-4830

Abstract

Abstract : Dimeric CPT (DCPT) could be largely encapsulated in polypeptide micelle RGD-PEG- g -PLL- b -PLeu (DRPPP) with redox-sensitive drug release capability, showing remarkable cellular uptake via RGD targeting, enhanced cytotoxicity and cell apoptosis. Abstract : Camptothecin (CPT) is a broad spectrum anticancer drug, but its application is limited due to the poor water solubility, lactone ring instability, and low drug loading potential. In this study, biocompatible cationic polypeptide-based micelles were developed to deliver dimeric CPT (DCPT) with the aim of overcoming the above-mentioned obstacles and achieving favorable therapeutic effects. Cationic polypeptide poly-lysine- block -poly-leucine (PLys- b -PLeu) was fabricated via the ring-opening polymerization of N -ε-carbobenzoxy-l -lysine (ε-Lys(Z)) andl -leucine (Leu) and further grafted with polyethylene glycol (PEG) and an arginine-glycine-aspartic acid (RGD) peptide. DCPT was synthesized by reacting CPT and 2-hydroxyethyl disulfide, and micelles were prepared using a dialysis method. The obtained DCPT-loaded RGD-PEG- g -poly-l -lysine- b -poly-l -leucine (DRPPP) micelles showed a high encapsulation efficiency of 89.7% and a high drug loading capacity of 46.1%. In addition, the DRPPP micelles remained stable under physiological conditions (PBS at a pH of 7.4) but showed rapid release when triggered by a reductive environment (PBS at a pH of 7.4 with 10 mM dithiothreitol). Compared to micelles without RGD decoration, the DRPPP micelles exhibited an increased cellular uptake through RGD targeting and were internalized into cells via caveolae-mediated endocytosis and macropinocytosis. Furthermore, the DRPPP micelles exerted an enhanced cytotoxicity against MDA-MB-231 cells compared to MCF-7 cells, which expressed less αv β3 receptors. Besides, the DRPPP micelles induced cell apoptosis and caused a decrease of mitochondrial membrane potential. These results indicate that dimeric camptothecin-loaded cationic polypeptide-based micelle is a promising strategy for cancer therapy.