Redox-responsive polyprodrug nanoparticles for targeted siRNA delivery and synergistic liver cancer therapy
Redox-responsive polyprodrug nanoparticles for targeted siRNA delivery and synergistic liver cancer therapy
复制标题
用于靶向 siRNA 递送和协同肝癌治疗的氧化还原响应聚前药纳米颗粒
DOI：
10.1016/j.biomaterials.2020.119760
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发表时间：
2020-03-01
期刊：
影响因子：
14
通讯作者：
Xu, Xiaoding
中科院分区：
文献类型：
--
作者：
Li, Senlin;Saw, Phei Er;Xu, Xiaoding
联合治疗已被开发为有效的癌症治疗的创新模式。然而，组合疗法的施用受到不同药物的不同药代动力学的限制。尽管许多纳米颗粒（NP）可以同步组合治疗剂向肿瘤细胞的递送，但它们的临床转化仍然受到挑战，这部分是由于精确控制组合治疗剂的负载以最大化治疗功效和次优NP性质的复杂性。在此，开发了一种新的氧化还原响应性聚前药纳米平台，用于靶向siRNA递送和协同癌症治疗。该NP平台由氧化还原响应性10-羟基喜树碱（HCPT）基聚前药（polyHCPT）作为内核、两亲性脂质-聚（乙二醇）（lipid-PEG）作为外壳和表面上的乳糖酸（LA）装饰制成。在siRNA负载和随后的全身给药后，所得NP平台可以在肿瘤组织中积累并通过LA和脱唾液酸糖蛋白（ASGP）受体之间的特异性识别靶向肝癌细胞。随着细胞质中高浓度的谷胱甘肽（GSH）破坏polyHCPT中的二硫键，完整的HCPT分子和包裹的B细胞淋巴瘤2（Bcl-2）siRNA（siBcl-2）可以快速释放，通过HCPT诱导细胞凋亡和siBcl-2同时沉默抗细胞凋亡基因来协同抑制肿瘤生长。
Combination therapy has been developed as an innovative modality for effective cancer therapy. However, the administration of combinatorial therapeutics is limited by the varying pharmacokinetics of different drugs. Although numerous nanoparticles (NPs) can synchronize the delivery of combinatorial therapeutics to tumor cells, their clinical translation is still challenged, which is partly due to the complexity to precisely control the loading of combinatorial therapeutics to maximize therapeutic efficacy and suboptimal NP properties. Herein, a new redox-responsive polyprodrug nanoplatform was developed for targeted siRNA delivery and synergistic cancer therapy. This NP platform is made with redox-responsive 10-hydroxycamptothecin (HCPT)-based polyprodrug (polyHCPT) as the inner core, amphiphilic lipid-poly (ethylene glycol) (lipid-PEG) as the outer shell, and lactobionic acid (LA) decoration on the surface. After siRNA loading and subsequent systemic administration, the resulting NP platform could accumulate in tumor tissues and target hepatoma cells via specific recognition between LA and asialoglycoprotein (ASGP) receptors. With the high concentration of glutathione (GSH) in the cytoplasm to break the disulfide bonds in the polyHCPT, intact HCPT molecules and encapsulated B-cell lymphoma 2 (Bcl-2) siRNA (siBcl-2) could be rapidly released, leading to the synergistic inhibition of tumor growth via the induction of apoptosis by HCPT and the concurrent silencing of the anti-apoptotic gene by siBcl-2.