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

Abstract

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, polycaprolac-tone-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°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 syringeability. 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.

Reversible hydrophobic ion-paring complex strategy to minimize acylation of octreotide during long-term delivery from PLGA microparticles

“…6 and 7. Our laboratory specializes in particle-in-gel formulations (Khurana et al, 2014; Mishra et al, 2011; Mitra and Mishra, 2011; Patel et al, 2014c; Patel et al, 2015; Patel et al, 2014d). Pentablock thermoresponsive polymer (PLA 250 -PCL 1250 -PEG 1500 -PCL 1250 -PLA 250 ) was utilized to sustain the release of octreotide.…”

“…Pentablock thermoresponsive polymer (PLA 250 -PCL 1250 -PEG 1500 -PCL 1250 -PLA 250 ) was utilized to sustain the release of octreotide. Preparation and characterization of gelling polymer has been published earlier from our laboratory (Patel et al, 2014d). MPs were suspended in an aqueous solution of pentablock polymer (20% w/w), which phase transform to gel at 37 °C to entrap MPs within gel matrix.…”

“…Pentablock polymer PLA 250 -PCL 1250 -PEG 1500 -PCL 1250 -PLA 250 was utilized to prepare thermoreversible gel solution. Preparation and characterization of gelling polymer has been published earlier from our laboratory (Patel et al, 2014d). Resulting MPs-in-gel suspension was incubated at 37°C for 2 min to form hydrogel followed by slow addition of 1.5 mL of PBS (pH 7.4) which was pre-incubated at 37°C.…”

Newer Trends in In Situ Gelling Systems for Controlled Ocular Drug Delivery

“…Patel et al [51], developed a biodegradable, injectable in situ thermosensitive hydrogel as depot for sustained delivery of protein therapeutics in posterior eye segment for treatment of neovascular diseases. Triblock (TB) polycaprolactonepolyethylene glycol-polycaprolactone [(PCL-PEG-PCL), BAB] and pentablock copolymers (PBCs) polylactic acid (PLA) [(PLA-PCL-PEG-PCL-PLA), CBABC] and [(PEG-PCL-PLA-PCL-PEG), ABCBA] were synthesized.…”

“…PBCs exhibited excellent cell viability and biocompatibility on human retinal pigment epithelial cell line and mouse macrophage cells. Since PBCs showed biodegradability, biocompatibility, thermosensitivity, ease of handling, hence it can be considered as potential biomaterial for sustained delivery of drugs not only for the posterior eye segment but also for anterior segment disorders [51].…”