Patel Sulabh P, Vaishya Ravi, Pal Dhananjay, Mitra Ashim K
Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, HSB 5258, 2464 Charlotte St., Kansas City, Missouri, 64108, USA.
AAPS PharmSciTech. 2015 Apr;16(2):327-43. doi: 10.1208/s12249-014-0196-6. Epub 2014 Oct 16.
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 ((1)H-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.
报道了新型可生物降解且生物相容的五嵌段（PB）共聚物，即聚乙醇酸 - 聚己内酯 - 聚乙二醇 - 聚己内酯 - 聚乙醇酸（PGA - PCL - PEG - PCL - PGA）和聚乳酸 - 聚己内酯 - 聚乙二醇 - 聚己内酯 - 聚乳酸（PLA - PCL - PEG - PCL - PLA）用于蛋白质持续递送的设计、合成及应用。这些PB共聚物可经设计实现蛋白质治疗药物向眼后段的持续递送。通过开环聚合反应合成了具有不同嵌段排列和分子量的PB共聚物，并采用质子核磁共振（(1)H - NMR）、凝胶渗透色谱（GPC）和X射线衍射（XRD）光谱进行表征。由于免疫球蛋白G（IgG）与贝伐单抗结构相似，故将其选作模型蛋白。阐述了聚合物分子量、组成和异构性对诸如包封率、载药量和体外释放曲线等制剂参数的影响。共聚物的结晶度和分子量对制剂参数有显著影响。通过圆二色性（CD）光谱证实了释放的IgG的二级结构。在人视网膜色素上皮细胞（ARPE - 19）和/或巨噬细胞系（RAW 264.7）上进行的体外细胞毒性、细胞活力和生物相容性研究表明PB共聚物是优异的生物材料。新型PB聚合物可能是满足持续释放蛋白质制剂未满足需求的答案。
