Dimeric camptothecin-loaded RGD-modified targeted cationic polypeptide-based micelles with high drug loading capacity and redox-responsive drug release capability

• Published in: Biomaterials science 2017-11, Vol.5 (12), p.251-251
• Main Authors: Guo, Zhaopei, Zhou, Xingzhi, Xu, Mengze, Tian, Huayu, Chen, Xuesi, Chen, Meiwan
• Format: Article
• Language: English
• Subjects: Apoptosis; Aspartic acid; Biocompatibility; Camptothecin - administration & dosage; Camptothecin - chemistry; Cationic polymerization; Cations - administration & dosage; Cations - chemistry; Dialysis; Drug Carriers - administration & dosage; Drug Carriers - chemistry; Drug delivery systems; Drug Liberation; Glycine; Humans; Lysine; MCF-7 Cells; Micelles; Neoplasms - drug therapy; Neoplasms - pathology; Oligopeptides - administration & dosage; Oligopeptides - chemistry; Oxidation-Reduction - drug effects; Peptides - administration & dosage; Peptides - chemistry; Polyethylene glycol; Polyethylene Glycols - administration & dosage; Polyethylene Glycols - chemistry; Polyleucine; Polypeptides; Receptors; Ring opening polymerization; Stability; Toxicity
• ISSN: 2047-4830; 2047-4849
• DOI: 10.1039/c7bm00791d

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 - -carbobenzoxy- l -lysine ( -Lys(Z)) and l -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 α v β 3 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. 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.