Dimeric camptothecin-loaded RGD-modified targeted cationic polypeptide-based micelles with high drug loading capacity and redox-responsive drug release capabilityElectronic supplementary information (ESI) available: Preparation of DCPT and its characterization; 1H NMR spectra of PLys-b-PLeu, PEG-g-PLys-b-PLeu, and RGD-PEG-g-PLys-b-PLeu in d-TFA; size distribution of DPP, DPPP, and DRPPP; stability of DCPT loaded micelles in 10% FBS within 48 h; in vitrorelease profile of CPT from DPP in PBS with or without DTT; cytotoxicity of MCF-7 and MDA-MB-231 cells treated with CPT and DCPT for 48 h and 72 h; cytotoxicity of MCF-7 and MDA-MB-231 cells treated with PP, PPP and RPPP for 48 h and 72 h; degree of polymerization of PLys-b-PLeu calculated by 1H NMR; EE%, DL%, particle size and zeta potential of DCPT and CPT loaded micelles; IC50values in MDA-MB-231 and MCF-7 cells. See 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 viathe 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 viacaveolae-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 αvβ3receptors. 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.