Mercer Iris G, Italiano Angelina N, Gazaryan Irina G, Steiner Aaron B, Kazakov Sergey V
Department of Chemistry and Physical Sciences, Pace University, Pleasantville, NY 10570, USA.
Department of Biology, Pace University, Pleasantville, NY 10570, USA.
Gels. 2023 Sep 25;9(10):782. doi: 10.3390/gels9100782.
Although biodegradable microgels represent a useful drug delivery system, questions remain regarding the kinetics of gel degradation and subsequent drug release. Spherical microgels (~Ø10-300 µm) were synthesized using an inverse suspension polymerization method. Specifically, acrylamide and acrylonitrile monomers were thermally co-polymerized with ,'-bis(acryloyl)cystamine as a cross-linker with disulfide bridges. The kinetics and mechanism of degradation of these cross-linked, degradable, fluorescently labeled microgels (PAAm-AN-BAC-FA) were quantitatively studied under confocal microscopy at various concentrations of glutathione (reducing agent) ranging from 0.06 to 91.8 mM. It was found that polymer network degradation via the cleavage of disulfide bonds was accompanied by two overlapping processes: diffusion-driven swelling and dissolution-driven erosion. A slow increase in microgel size (swelling) resulted from partial de-cross-linking in the bulk of the microgel, whereas a faster decrease in fluorescence intensity (erosion) resulted from the complete cleavage of disulfide bonds and the release of uncleaved polymeric chains from the microgel immediate surface into the solution. Swelling and erosion exhibited distinct kinetics and characteristic times. Importantly, the dependence of kinetics on glutathione concentration for both swelling and erosion suggests that degradation would occur faster in cancer cells (higher concentration of reductants) than in normal cells (lower concentration of reductants), such that drug release profiles would be correspondingly different. A greater comprehension of microgel degradation kinetics would help in (i) predicting the drug release profiles for novel multifunctional drug delivery systems and (ii) using redox-sensitive degradable hydrogel particles to determine the concentrations of reducing agents either in vitro or in vivo.
尽管可生物降解的微凝胶是一种有用的药物递送系统，但关于凝胶降解动力学及随后的药物释放仍存在问题。使用反相悬浮聚合法合成了球形微凝胶（直径约10 - 300 µm）。具体而言，丙烯酰胺和丙烯腈单体与作为具有二硫键交联剂的,'-双（丙烯酰基）胱胺进行热共聚。在共聚焦显微镜下，于0.06至91.8 mM的各种谷胱甘肽（还原剂）浓度下，对这些交联、可降解、荧光标记的微凝胶（PAAm - AN - BAC - FA）的降解动力学和机制进行了定量研究。结果发现，通过二硫键断裂引起的聚合物网络降解伴随着两个重叠过程：扩散驱动的溶胀和溶解驱动的侵蚀。微凝胶尺寸的缓慢增加（溶胀）是由于微凝胶内部的部分去交联，而荧光强度的更快降低（侵蚀）是由于二硫键的完全断裂以及未断裂的聚合物链从微凝胶表面立即释放到溶液中。溶胀和侵蚀表现出不同的动力学和特征时间。重要的是，溶胀和侵蚀的动力学对谷胱甘肽浓度的依赖性表明，降解在癌细胞（还原剂浓度较高）中比在正常细胞（还原剂浓度较低）中发生得更快，从而药物释放曲线也会相应不同。对微凝胶降解动力学有更深入的理解将有助于（i）预测新型多功能药物递送系统的药物释放曲线，以及（ii）使用氧化还原敏感的可降解水凝胶颗粒在体外或体内测定还原剂的浓度。
