Morphologic design of sugar-based polymer nanoparticles for delivery of antidiabetic peptides
Morphologic design of sugar-based polymer nanoparticles for delivery of antidiabetic peptides
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DOI：
10.1016/j.jconrel.2021.04.006
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发表时间：
2021-04-18
影响因子：
10.8
通讯作者：
Wooley, Karen L.
中科院分区：
文献类型：
--
作者：
Elsabahy, Mahmoud;Song, Yue;Wooley, Karen L.
由生物相容性糖基聚合物构成的不同形态（球形、圆柱形和血小板样）的两性离子聚合物纳米颗粒被设计用于延长短效和长效胰岛素肽的药理活性，从而为能够减少给药频率和提高患者依从性的治疗系统提供潜力。合成了两性离子聚（d -碳酸葡萄糖）和半晶聚乳酸段组成的两亲性嵌段共聚物，并调整了各自的嵌段长度比，以形成具有不同形貌的纳米级组装体。负载胰岛素的纳米颗粒与未负载的纳米颗粒具有相似的大小和形态。激光扫描共聚焦显微镜成像血管平滑肌细胞和成纤维细胞经过LIVE/DEAD (R)染色和fitc -胰岛素负载纳米颗粒处理后的三维球体显示，在两种细胞系中，不同形态的纳米结构具有较高的生物相容性和显著的细胞内胰岛素摄取。在糖尿病大鼠模型中，短效胰岛素和长效甘精胰岛素与纳米颗粒结合可延长降糖活性。在糖尿病大鼠皮下注射后，与游离胰岛素和甘精胰岛素相比，不同形态的胰岛素和甘精胰岛素负载纳米颗粒的药理学可用性分别增加了2.6倍和1.7倍。总之，可忽略的细胞毒性、免疫毒性和纳米颗粒对细胞因子的最小吸附（正如我们之前的研究所证明的那样）为生物相容性纳米结构提供了令人兴奋和有希望的证据，这些纳米结构有望进一步开发用于糖尿病的治疗。
Zwitterionic polymer nanoparticles of diverse morphologies (spherical, cylindrical, and platelet-like) constructed from biocompatible sugar-based polymers are designed to extend the pharmacological activities of short- and long-acting insulin peptides, thereby providing potential for therapeutic systems capable of reducing the frequency of administration and improving patient compliance. Amphiphilic block copolymers composed of zwitterionic poly(D-glucose carbonate) and semicrystalline polylactide segments were synthesized, and the respective block length ratios were tuned to allow formation of nanoscopic assemblies having different morphologies. Insulin-loaded nanoparticles had similar sizes and morphologies to the unloaded nanoparticle counterparts. Laser scanning confocal microscopy imaging of three-dimensional spheroids of vascular smooth muscle cells and fibroblasts after treatment with LIVE/DEAD (R) stain and FITC-insulin-loaded nanoparticles demonstrated high biocompatibility for the nanoconstructs of the various morphologies and significant intracellular uptake of insulin in both cell lines, respectively. Binding of short-acting insulin and long-acting insulin glargine to nanoparticles resulted in extended hypoglycemic activities in rat models of diabetes. Following subcutaneous injection in diabetic rats, insulin- and insulin glargine-loaded nanoparticles of diverse morphologies had demonstrated up to 2.6-fold and 1.7-fold increase in pharmacological availability, in comparison to free insulin and insulin glargine, respectively. All together, the negligible cytotoxicity, immunotoxicity, and minimal cytokine adsorption onto nanoparticles (as have been demonstrated in our previous studies) provide exciting and promising evidence of biocompatible nanoconstructs that are poised for further development toward the management of diabetes.