State Key Laboratory of Natural Medicines and Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China.
State Key Laboratory of Natural Medicines and Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China; Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA.
J Control Release. 2018 Dec 28;292:78-90. doi: 10.1016/j.jconrel.2018.02.036. Epub 2018 Feb 27.
In present study, gene concentrated as well as bioreduction-ruptured nanogel with local enrichment positive charge while low cytotoxicity was developed for Bcl2 siRNA delivery featured in intracellular switch on/off controlled release. Dynamic covalent bond crosslinked nanogel was formed by thiolated PEI of 1.8 kDa(PEI-1.8 kDa)and biodegradable dextrin. Once nanogel was uptake by tumor cells, high concentration of glutathione (GSH) in cytosol could bioreducible -degrade and rupture the crosslink of this dextrin nanogel (DSP) into hypotoxic PEI-1.8 kDa and dextrin, following by burst release of packed siRNA and minimizing the restriction of polymer material for siRNA transcription. This switch on/off siRNA release strategy for gene therapy exhibited equal level of the deregulation of Bcl2 protein expression determined by western blot analysis compared with cationic PEI with 25 kDa molecular weight (PEI-25 kDa) in vitro. Moreover, the gene concentrated DSP based on hypotoxic PEI-1.8 kDa and biodegradable dextrin could be administrated intravenously for systematic therapy on safely. Tumor suppression study of DSP also exhibited a superior antitumor activity in 4T1-luc tumor cell bearing BALB/C mice. Furthermore, it exhibited lower cytotoxicity, almost none hemotoxicity, moreover avoiding recognition and clearance by RES system in healthy mice. Overall, these findings suggest that this reduction-sensitive while bioreduction-ruptured polymer nanogel is an innovative strategy and holds great promise for gene and drug delivery.
在本研究中，开发了一种基因浓缩和生物还原断裂纳米凝胶，其具有局部富集正电荷且细胞毒性低的特点，可用于 Bcl2siRNA 递释，其特点是细胞内开关控制的控制释放。通过巯基化的 1.8kDa（PEI-1.8kDa）和可生物降解的糊精的聚亚乙基亚胺形成动态共价键交联纳米凝胶。一旦纳米凝胶被肿瘤细胞摄取，细胞质中高浓度的谷胱甘肽（GSH）可以生物还原降解并破坏这种糊精纳米凝胶（DSP）的交联，形成低细胞毒性的 1.8kDa 聚亚乙基亚胺和糊精，随后包封的 siRNA 爆发释放，并最大限度地减少聚合物材料对 siRNA 转录的限制。这种开关式 siRNA 释放策略用于基因治疗，与 25kDa 分子量的阳离子聚亚乙基亚胺（PEI-25kDa）相比，通过 Western blot 分析确定 Bcl2 蛋白表达的失调水平相等。此外，基于低细胞毒性的 1.8kDa 聚亚乙基亚胺和可生物降解的糊精的基因浓缩 DSP 可通过静脉内给药进行安全的系统治疗。DSP 的肿瘤抑制研究也在携带 4T1-luc 肿瘤细胞的 BALB/C 小鼠中表现出优异的抗肿瘤活性。此外，它表现出较低的细胞毒性，几乎没有血液毒性，并且在健康小鼠中避免被 RES 系统识别和清除。总的来说，这些发现表明，这种还原敏感且生物还原断裂的聚合物纳米凝胶是一种创新策略，为基因和药物传递提供了巨大的前景。
