Department of Chemical Engineering, Queen's University, Kingston, Ontario K7L 3N6, Canada; Human Mobility Research Centre, Kingston General Hospital, Kingston, Ontario K7L 2V7, Canada.
Department of Biomedical and Molecular Sciences, Queen's University, Kingston K7L 3N6, Canada.
Int J Pharm. 2020 Nov 30;590:119965. doi: 10.1016/j.ijpharm.2020.119965. Epub 2020 Oct 9.
Viscous liquid degradable polymers have advantages as drug depots for sustained protein delivery. We have created a new aliphatic polycarbonate for this purpose, poly(trimethylene carbonate-co-5-hydroxy trimethylene carbonate), which upon degradation retains a near neutral micro-environmental pH. As such, this copolymer is highly suited to the delivery of acid sensitive proteins. We show that the mechanism of protein release from this liquid copolymer is consistent with the formation of super-hydrated regions as a result of the osmotic activity of the solution formed upon distributed protein particle dissolution. Protein release can be manipulated by controlling polymer hydrophobicity which can be adjusted by molecular weight and choice of initiator. Moreover, protein release is highly dependent on protein solubility which impacts the osmotic activity of the solution formed upon dissolution of the protein particles while protein molecular size and isoelectric point are not as influential. As demonstrated by the release of highly bioactive vascular endothelial growth factor, formulations of this copolymer are suitable for prolonged delivery of protein therapeutics.
粘性液体可降解聚合物作为蛋白质的持续释放药物载体具有优势。为此，我们开发了一种新型脂肪族聚碳酸酯，即聚（三亚甲基碳酸酯-5-羟三亚甲基碳酸酯），其在降解后仍保持接近中性的微环境 pH 值。因此，该共聚物非常适合输送对酸敏感的蛋白质。我们表明，这种液体共聚物中蛋白质释放的机制与由于形成的溶液的渗透压活性而形成的超水合区域的形成一致，该溶液是在分散的蛋白质颗粒溶解时形成的。通过控制聚合物疏水性可以控制蛋白质释放，而聚合物疏水性可以通过分子量和引发剂的选择进行调节。此外，蛋白质释放高度依赖于蛋白质溶解度，这会影响蛋白质颗粒溶解时形成的溶液的渗透压活性，而蛋白质分子大小和等电点的影响则较小。如通过高生物活性血管内皮生长因子的释放所证明的，该共聚物的制剂适合于蛋白质治疗药物的长期输送。
