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Novel Pentablock Copolymer-Based Nanoparticulate Systems for Sustained Protein Delivery

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Abstract

The design, synthesis, and application of novel biodegradable and biocompatible pentablock (PB) copolymers, i.e., polyglycolic acid-polycaprolactone-polyethylene glycol-polycaprolactone-polyglycolic acid (PGA-PCL-PEG-PCL-PGA) and polylactic acid-polycaprolactone-polyethylene glycol-polycaprolactone-polylactic acid (PLA-PCL-PEG-PCL-PLA) for sustained protein delivery, are reported. The PB copolymers can be engineered to generate sustained delivery of protein therapeutics to the posterior segment of the eye. PB copolymers with different block arrangements and molecular weights were synthesized by ring-opening polymerization and characterized by proton nuclear magnetic resonance (1H-NMR), gel permeation chromatography (GPC), and X-ray diffraction (XRD) spectroscopy. Immunoglobulin G (IgG) was selected as a model protein due to its structural similarity to bevacizumab. The influence of polymer molecular weight, composition, and isomerism on formulation parameters such as entrapment efficiency, drug loading, and in vitro release profile was delineated. Crystallinity and molecular weight of copolymers exhibited a substantial effect on formulation parameters. A secondary structure of released IgG was confirmed by circular dichroism (CD) spectroscopy. In vitro cytotoxicity, cell viability, and biocompatibility studies performed on human retinal pigment epithelial cells (ARPE-19) and/or macrophage cell line (RAW 264.7) demonstrated PB copolymers to be excellent biomaterials. Novel PB polymers may be the answer to the unmet need of a sustained release protein formulation.

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ACKNOWLEDGMENTS

This study was supported by NIH R01 EY09171-14 and NIH RO1 EY10659-12. We are greatly thankful to Dr. James Murowchick (Department of Geosciences, UMKC) for helping in XRD analysis, Dr. Zhonghua Peng (Department of Chemistry, UMKC) for his assistance in GPC analysis, and Dr. Natalya Shipulina (School of Biological Sciences, UMKC) for helping us during CD spectroscopy analysis.

Conflict of Interest

Authors have declared a conflict of interest with I-Novion Inc.

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Correspondence to Ashim K. Mitra.

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Patel, S.P., Vaishya, R., Pal, D. et al. Novel Pentablock Copolymer-Based Nanoparticulate Systems for Sustained Protein Delivery. AAPS PharmSciTech 16, 327–343 (2015). https://doi.org/10.1208/s12249-014-0196-6

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  • DOI: https://doi.org/10.1208/s12249-014-0196-6

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