Three-armed RGD-decorated Star-PLA-PEG Nanoshuttle for Antitumoral Drugs Delivery

A novel star-shaped amphiphilic copolymer based on poly(lactide)-block-poly(ethylene glycol) (PLAPEG) was synthesized and decorated with the tumor-targeting ligand cyclic-RGDyK peptide (Arg-Gly- Asp-D-Tyr-Lys) to be eventually formulated in polymeric micelles incorporating suitable anticancer drugs (i.e., Docetaxel, DTX, and Doxorubicin, Dox). The star-PLA-PEG was obtained in a multi-step synthesis by sequentially combining a typical ring-opening polymerization (ROP) of lactide, using glycerol as the core, with proper copper-catalyzed azide-alkyne cycloaddition (CuAAC) reactions to functionalize the three arms of PLA with suitable components (i.e., PEG and RGD) for drug delivery purposes. The combination of ROP and click chemistry1 allowed an optimal control over the molecular weight, the hydrophobic:hydrophilic balance, the molecular weight distributions, and the accessibility of chain-end functionalities. DTX and Dox were efficiently encapsulated into the star-PLA-PEG-RGD micelles by nanoprecipitation and the physicochemical properties of both “empty” (RGD-NanoStar) and drug-loaded (RGD-NanoStar/DTX and RGD-NanoStar/Dox) micelles were evaluated in terms of CMC, size and zeta potential. The antitumoral efficiency were studied in vitro on different tumoral cell lines (i.e., U87 Human Glioblastoma and MDA-MB 468 Human Breast Adenocarcinoma for RGDNanoStar/ DTX; osteosarcoma cell lines MG-63, Saos-2 and U2-OS for RGD-NanoStar/Dox).