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Sulabh Patel, Gyan Mishra, Viral Tamboli, Ashim Mitra; Novel pentablock copolymers as a nanotechnology platform for controlled ocular delivery of proteins. Invest. Ophthalmol. Vis. Sci. 2013;54(15):1388. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Current macromolecular delivery in the treatment of wet-AMD requires frequent intravitreal injections to maintain therapeutic levels at retina/choroid. Frequent administrations can cause potential complications like endophthalmitis, retinal detachment, retinal hemorrhage, and patient noncompliance. The objective of this research is to synthesize and evaluate novel tailor-made pentablock (PB) copolymers for the controlled and non-invasive delivery of macromolecules in the treatment of posterior segment diseases.
We have synthesized novel biodegradable PB copolymers by sequential ring opening polymerization. Different ratio and MW of each block (polyglycolide, polyethylene glycol, polylactide and polycaprolactone) were selected for synthesis to optimize the release profile of FITC-BSA, IgG and avastin from nanoparticles and thermosensitive gel. Nanoparticles were characterized for particle size, poly dispersity, entrapment efficiency and drug loading. In vitro release studies of FITC-BSA, IgG and avastin from nanoparticles alone and nanoparticles suspended in thermosensitive gel were performed in PBS (0.1M, pH 7.4) at 37 C. CD spectroscopy, ELISA, cell proliferation and cell invasion techniques were employed to evaluate conformation and binding affinity of released IgG and avastin. In vitro cell viability (MTS and LDH assay) and biocompatibility studies were performed on various ocular (ARPE 19, SIRC and HCEC) and macrophage cell lines (RAW 264.7), respectively.
FITC-BSA and IgG loaded nanoparticles prepared from PB colpolymers exhibited ~ 40% and ~ 25% of burst release within first 2 days followed by sustained release up to 40 and 52 days, respectively. IgG loaded nanoparticles suspended in thermosensitive gel demonstrated continuous zero order release up to 62 days. Moreover, CD spectroscopy and ELISA showed retention of conformation and binding affinity of released IgG. Avastin loaded nanoparticles demonstrated similar patterns of burst release and sustained release as of IgG loaded nanoparticles. Furthermore, cell migration and cell invasion assay confirmed retention of biological activity of the avastin. PB copolymers exhibited excellent biocompatibility with negligible toxicity.
This approach can act as a platform for ocular delivery of therapeutic macromolecules, which can minimize the side effects associated with frequent intravitreal injections.
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