Design of Multi-Functional SplitCore HBV Capsids for Precisely Controlled Multi-siRNA Delivery in Cancer Therapeutics

设计多功能 SplitCore HBV 衣壳，用于癌症治疗中精确控制的多 siRNA 递送

• 批准号: 1609621
• 负责人: Wilfred Chen
• 金额: $ 36万
• 依托单位: University of Delaware
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-15 至 2021-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1609621&HistoricalAwards=false
• 关键词: Design; Multi; Functional; SplitCore; HBV

Nontechnical descriptionBy 2030, there could be 27 million incident cases of cancer worldwide. Gene silencing therapies offer unique promise for cancer treatment by providing highly potent and target-specific silencing of genes during cancer progression. The major technological hurdles confronting the use of gene silencing for cancer treatment are the needs for improved delivery and protection from rapidly degradation under physiological conditions. To tackle this problem, this program will design multi-functional Hepatitis B Virus (HBV) capsids suitable for cell-specific delivery by targeting receptors that are highly expressed on the surface of tumors. HBV capsids are designed to release the gene silencing agents inside of cells based on pH changes. The students trained on this project will be exposed to multi-disciplinary training in the context of research that is anticipated to significantly advance biomaterials capabilities. Technical descriptionThe development of effective therapeutic vehicles for siRNA delivery is of essential importance in cancer treatment. Virus-like-particles (VLPs) based on the SplitCore HBV technology are ideally suited for this purpose by providing a transformative approach to attach four unique decorations (3 exterior, 1 interior) to each HBV monomer into a highly modular nanoplatform suitable for customizable cell targeting and siRNA capture/release. This significant advance can enable key increases in both cell specificity and therapeutic efficacy through incorporation of well-defined combinations of targeting ligands as well as siRNAs, ultimately creating hybrid structures that fuse the delivery efficiency of viruses to the design versatility of non-viral vehicles. The simplicity of the design allows the creation of highly adaptable, multi-functional HBV capsids suitable for a range of cancer targets.

非技术描述在2030年，全球可能有2700万例癌症事件。基因沉默疗法通过在癌症进展过程中提供了对基因的高度和靶标的沉默，为癌症治疗提供了独特的希望。使用基因沉默来治疗基因治疗的主要技术障碍是在生理条件下改善分娩和免受快速降解的需求。为了解决这个问题，该程序将设计多功能丙型肝炎病毒（HBV）衣壳，适用于在肿瘤表面高表达的受体，适合于细胞特异性递送。 HBV衣壳旨在根据pH变化释放细胞内部基因沉默剂。接受该项目的培训的学生将在研究的背景下接受多学科培训，这些培训预计可以显着提高生物材料能力。技术描述在癌症治疗中开发有效的siRNA递送治疗工具至关重要。基于分裂孔HBV技术的病毒样粒子（VLP）非常适合此目的，它通过提供一种变革性的方法来将四个独特的装饰（3个外部，1个内部）连接到每个HBV单体中靶向和siRNA捕获/释放。这一重大进展可以通过纳入靶向配体和siRNA的定义明确的组合以及最终创建融合病毒效率与非病毒车辆设计的递送效率来实现细胞特异性和治疗功效的关键提高。 设计的简单性允许创建适用于一系列癌症靶标的高度适应性，多功能的HBV衣壳。