Abstract
The objective of this research article is to report the synthesis and evaluation of novel pentablock copolymers for controlled delivery of macromolecules in the treatment of posterior segment diseases. Novel biodegradable PB copolymers were synthesized by sequential ring-opening polymerization. Various ratios and molecular weights of each block (polyglycolic acid, polyethylene glycol, polylactic acid, and polycaprolactone) were selected for synthesis and to optimize release profile of FITC-BSA, IgG, and bevacizumab from nanoparticles (NPs) and thermosensitive gel. NPs were characterized for particle size, polydispersity, entrapment efficiency, and drug loading. In vitro release study of proteins from NPs alone and composite formulation (NPs suspended in thermosensitive gel) was performed. Composite formulations demonstrated no or negligible burst release with continuous near zero-order release in contrast to NPs alone. Hydrodynamic diameter of protein therapeutics and hydrophobicity of PB copolymer exhibited significant effect on entrapment efficiency and in vitro release profile. CD spectroscopy confirmed retention of structural conformation of released protein. Biological activity of released bevacizumab was confirmed by in vitro cell proliferation and cell migration assays. It can be concluded that novel PB polymers can serve a platform for sustained delivery of therapeutic proteins.
Highlights
Diabetic retinopathy and age-related macular degeneration (AMD) are primary vision threatening ocular diseases which affect retinal pigment epithelium (RPE), macular region of the retina, choriocapillary, and Bruch’s membrane
In order to achieve continuous zero-order drug release, we have prepared and characterized a novel composite formulation comprising drug-loaded NPs suspended in thermosensitive gelling aqueous solution
Purified TB copolymers were utilized for the synthesis of respective PB copolymers, that is, PB-A (PGA-PCL-polyethylene glycol (PEG)-PCL-polyglycolic acid (PGA)) and PB-B (PLA-PCL-PEG-PCL-polylactic acid (PLA))
Summary
Diabetic retinopathy and age-related macular degeneration (AMD) are primary vision threatening ocular diseases which affect retinal pigment epithelium (RPE), macular region of the retina, choriocapillary, and Bruch’s membrane. AMD is typically observed in two forms, “wet” and “dry.” In wet AMD, choroidal neovascularization (CNV) occurs due to the leakage of blood and other fluids into the subretinal space which leads to scar formation eventually causing irreversible vision loss [1]. Many investigators reported active involvement of vascular endothelial growth factor (VEGF), a naturally occurring lipoprotein in various pathophysiological processes including AMD and diabetic retinopathy (DR) [2]. Anti-VEGF antibodies such as bevacizumab and ranibizumab are indicated for the treatment of wet AMD. Due to shorter intravitreal halflife of bevacizumab [4], current treatment requires frequent intravitreal injections to maintain therapeutic levels at retina/choroid. Frequent administrations are inconvenient and cause potential complications like retinal hemorrhage, retinal detachment, endophthalmitis, and more importantly patient noncompliance [5,6,7]
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