Novel Thermosensitive Pentablock Copolymers for Sustained Delivery of Proteins in the Treatment of Posterior Segment Diseases

Biodegradable and injectable in situ thermosensitive hydrogels were investigated for sustained delivery of protein therapeutics in the treatment of ocular posterior segment neovascular diseases. A series of triblock (TB, polycaprolactone- polyethylene glycol-polycaprolactone (PCL-PEG-PCL), B-A-B) and pentablock copolymers (PBCs) (polylactic acid (PLA)-PCL-PEG-PCL-PLA (C-B-A-B-C) and PEG-PCL-PLA-PCL-PEG (A-B-C-B-A)) were synthesized and evaluated for their thermosensitive behavior. Effects of molecular weight, hydrophobicity and block arrangement on polymer crystallinity, sol-gel transition, micelle size, viscosity and in vitro drug release were examined. Results from sol-gel transition studies demonstrated that aqueous solutions of block copolymers can immediately transform to hydrogel upon exposure to physiological temperature. PBC provide significantly longer sustained release (more than 20 days) of IgG relative to TB copolymers. Moreover, kinematic viscosity of aqueous solution at 25 degrees C for A-B-C-B-A type of PBCs was noticeably lower than the TB (B-A-B) copolymers and other PBCs with C-B-A-B-C block arrangements suggesting desired syringe-ability. The presence of PLA blocks in PBCs (C-B-A-B-C and A-B-C-B-A) significantly reduces crystallinity. Hence, it is anticipated that PBCs will have a faster rate of degradation relative to PCL-PEG-PCL based TB copolymers. PBCs also exhibited excellent cell viability and biocompatibility on ARPE-19 (human retinal pigment epithelial cell line) and RAW-264.7 (mouse macrophage cells), likely rendering it safe for ocular applications. Owing to biodegradability, thermosensitivity, ease of handling and biocompatibility PBC hydrogels can be considered as promising biomaterial for sustained delivery of protein therapeutics to the back of the eye.