Poly (propargyl L-glutamate) Based Linear-Dendritic Block Copolymers As pH-Responsive Hydrophobic Drug Carrier

To design biocompatible, pH-responsive and long-circulating nanoparticulate drug delivery systems, we have coupled a hydrophobic poly (propargyl L-glutamate) (PPLG) linear polypeptide block to a hydrophilic poly (ester) dendron by highly efficient thiol-maleimide chemistry. The propargyl side-chains of the polypeptide segment were attached to diethylamine moieties through Cu-mediated azide-alkyne ‘click’ cycloaddition. The synthesized block copolymers with linear-dendritic topology were found to self-assemble and disassemble into stable nanoparticles in a pH-responsive manner over a range of biologically relevant conditions. These sterically stabilized block copolymer assemblies were able to encapsulate both hydrophilic and hydrophobic anticancer agents without compromising their cytotoxic property, and undergo controlled release at the pH of the endosomal compartments within which the nanoparticles accumulate.  The dendritic block is designed to present a cluster arrangement of ligands on the surfaces of the vesicles generated by these block copolymers, thus enhancing targeted tumor uptake. Whole-animal fluorescence imaging showed that, when administered systemically to BALB/c mice, Cy 5.5 conjugated linear-dendritic nanoparticles persisted in blood for a period of more than 30h with substantially controlled liver accumulation.