Therapeutic potential of functionalized siRNA nanoparticles on regression of liver cancer in experimental mice
Therapeutic potential of functionalized siRNA nanoparticles on regression of liver cancer in experimental mice
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DOI：
10.1038/s41598-019-52142-4
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发表时间：
2019-11-01
影响因子：
4.6
通讯作者：
Ansari, Mohammad Azam
中科院分区：
文献类型：
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作者：
Khan, Azmat Ali;Alanazi, Amer M.;Ansari, Mohammad Azam
短干扰RNA（Short interfering RNA，siRNA）具有沉默特定基因的特殊能力。为了增加siRNA的稳定性、转运及其被肿瘤细胞的摄取，有效递送至适当的靶细胞是基于siRNA的治疗的主要挑战。在本研究中，一种有效、安全和生物相容的生存素siRNA封装的、GalNAc修饰的PEG化PLGA纳米缀合物（NC），即，将GalNAc@ PEG@siRNA-PLGA工程化，并评价它们在荷HCC实验小鼠中靶向递送的协同抗肿瘤功效。对GalNAc@PEG@siRNA-PLGA NC的尺寸、生物利用度、毒性和生物相容性进行表征。考虑基因沉默、细胞凋亡、组织病理学和治疗小鼠的存活率，评价其抗肿瘤潜力。肝细胞的异常积累、生存素表达的减少和肿瘤大小的显著消退证实了ASGPR介导的配体锚定的NC的摄取和生存素基因的靶向沉默。增加的DNA片段化和caspase-3、Bax和Bcl-2因子的潜在调节指定了有助于显著抑制HCC进展的凋亡诱导。多功能NC的潜在同步和肿瘤选择性递送表明了朝向靶位点的有效载荷，增加了癌细胞的凋亡并改善了治疗动物的存活率。
Short interfering RNA (siRNA) possesses special ability of silencing specific gene. To increase siRNA stability, transportation and its uptake by tumor cells, effective delivery to the appropriate target cells is a major challenge of siRNA-based therapy. In the present study, an effective, safe and biocompatible survivin siRNA encapsulated, GalNAc decorated PEGylated PLGA nanoconjugates (NCs) viz., GalNAc@ PEG@siRNA-PLGA were engineered and their synergistic antitumor efficacy was evaluated for targeted delivery in HCC bearing experimental mice. GalNAc@PEG@siRNA-PLGA NCs were characterized for size, bioavailability, toxicity and biocompatibility. Their antitumor potential was evaluated considering gene silencing, apoptosis, histopathology and survival of treated mice. Exceptional accumulation of hepatocytes, reduction in survivin expression and prominent regression in tumor size confirmed the ASGPR-mediated uptake of ligand-anchored NCs and silencing of survivin gene in a targeted manner. Increased DNA fragmentation and potential modulation of caspase-3, Bax and Bcl-2 factors specified the induction of apoptosis that helped in significant inhibition of HCC progression. The potential synchronous and tumor selective delivery of versatile NCs indicated the effective payloads towards the target site, increased apoptosis in cancer cells and improved survival of treated animals.