Poly(L-Glutamic Acid)-Based Brush Copolymers: Fabrication, Self-assembly, and Evaluation as Efficient Nanocarriers for Cationic Protein Drug Delivery

Protein drugs were considered to be the first choice to treat many human diseases, but their clinical application was usually limited by their short half-life and lack of validated targeted therapy. Here, a series of folate-functionalized poly(ethylene glycol)-b-(poly(2-aminoethyl-L-glutamate)-g-poly(L-glutamic acid))s (FA-PEG-b-(PELG-g-PLGA)s) were designed as tumor-targeted carriers for cationic protein delivery. Compared with traditional copolymers consisting of PEG and linear charged hydrophilic blocks, FA-PEG-b-(PELG-g-PLGA) with brush-like polyelectrolyte segments were beneficial to improving their electrostatic interactions with loading protein molecules, thus increasing drug-loading stability and protecting encapsulated proteins from degradation. The designed polymer brushes could efficiently encapsulate cytochrome C (CytC), a cationic model protein, to form polyion complex (PIC) micelles with an average particle size of approximately 200 nm. An in vitro drug release study showed that the drug-loading stability of the formed PIC micelles was largely improved. The functionalization of the block copolymer carriers with a targeting folate group enhanced the tumor cell growth inhibition and total apoptotic rates induced by CytC. Our results shed light on the unique advantages of brush-like polymer carriers in delivering cationic proteins, and the poly(L-glutamic acid)-based linear-brush diblock copolymers could be applied as a versatile delivery platform for molecular targeting in cancer therapy.