Facile synthesis of RGD-conjugated unimolecular micelles based on a polyester dendrimer for targeting drug delivery

Arginyl-glycyl-aspartic acid (RGD)-conjugated core-shell amphiphilic copolymers consisting of a polyester dendrimer poly(propargyl alcohol-4-mercaptobutyric acid) (PPMA) core and hydrophilic poly(ethylene glycol) (PEG) shells (PPMA-MPEG/PEG-RGD) were synthesized as unimolecular micelles for targeted drug delivery. During the synthesis, the PPMA core was firstly constructed at the end of a polystyrene (PS) support via the combination of a highly efficient thio-yne click reaction and esterification. The presence of PS segments in l-PS-PPMA hybrid copolymers facilitated the easy separation of the product from the excessive unreacted monomers by simple precipitation. After five reaction cycles, the fifth-generation PPMA with 64 terminal carboxylic acid groups (PPMA(G5)64-COOH) was formed, in which the characteristic alkoxyamine linker between PS and PPMA segments was easily cleaved at an elevated temperature. The resultant PPMA-64-COOH was further coupled with MPEG/MAPEG followed by functionalization with RGD-SH to produce the targeted copolymer PPMA-MPEG/PEG-RGD. Due to the unique single molecular core-shell architecture, PPMA-MPEG/PEG-RGD copolymers exist as stable unimolecular micelles in aqueous solution. In addition, the hydrophobic core in PPMA-MPEG/PEG-RGD unimolecular micelles exhibited strong capability for the encapsulation of hydrophobic anticancer drugs, and it showed the pH-dependent controlled release behavior of the payload. Furthermore, in vitro cytotoxicity assay revealed the good biocompatibility of PPMA-MPEG/PEG-RGD unimolecular micelles. These results indicated that as-developed unimolecular micelles are promising candidates as tumor-targeted drug delivery nanocarriers.