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Mary Joseph, Sulabh P Patel, VIBHUTI AGRAHARI, Ashim K Mitra; Pentablock Copolymer nano formulation for controlled Ocular Delivery of Protein Therapeutics. Invest. Ophthalmol. Vis. Sci. 2014;55(13):4629.
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Recurrent intravitreal injections are obligatory to maintain therapeutic levels at choroid and retina for wet-MAD treatment. Several administrations of drugs to retina may result to possible impediments such as retinal hemorrhage, retinal detachment, endophthalmitis, and patient nonconformity. The objective of this research is to synthesize and assess pentablock (PB) copolymers for the precise and non-aggressive delivery of macromolecules in the treatment of posterior segment diseases of the eye.
Unique biodegradable pentablock copolymers were synthesized using sequential ring opening polymerization process. Different ratio and molecular weight of each block (polylactide, polyglycolide, polyethylene glycol and polycaprolactone) were used for synthesis to improve the release profile of Human Immunoglobulin (IgG) from nanoparticles formulation. Nanoparticles were characterized by particle size, entrapment efficiency, and drug loading. Circular Dichroism spectroscopy and ELISA techniques were used to assess configuration and binding affinity of the released IgG. After 48 hours exposure of PB copolymers to human conjunctiva epithelial cells (HCEC) and macrophage (RAW 264.7) cell line, in vitro cell viability studies were performed using LDH and MTS assays. In Vitro release studies were executed in PBS (0.1M, pH 7.4) at 37°C. Furthermore, biocompatibility of pentablock copolymers was evaluated by exposing polymers to RAW 264.7 for 24 hours and release of inflammatory mediators; IL 1β, IL 6, and TNF α were examined by ELISA method.
Characterization of nanoparticles demonstrated discrete effects as a result of different molecular weights as well as type of end blocks of pentablock copolymers on several pre-formulation parameters including burst release effect, drug entrapment efficiency, and drug loading capacity. Pentablock copolymers demonstrated more than 90% viability in HCEC and RAW 264.7 cell lines. Circular Dichroism spectroscopy and ELISA showed retention of conformation and binding affinity of released IgG. Pentablock copolymers showed negligible release amount of inflammatory mediators from RAW 264.7 cell line.
This methodology can be used for ocular delivery of therapeutic macromolecules, hence reduce side effects related with recurrent intravitreal injections.
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