Saccharide Functionalization of Bola-amphiphiles for siRNA Delivery

用于 siRNA 递送的 Bola 两亲物的糖功能化

• 批准号: 8981788
• 负责人: Nathan John Oldenhuis
• 金额: $ 3.73万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-07 至 2018-07-06
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8981788
• 关键词: Address; Affect; Affinity; Amines; Amino Acids; Architecture; Asses; Biological Assay; Blood Proteins; Cell Culture Techniques; Cells; Charge; Complex; Confocal Microscopy; Cytoplasm; Dendrimers; Diabetes Mellitus; Disease; Exhibits; Gene Targeting; Hereditary Disease; Human; In Vitro; Investigation; Label; Lead; Lectin; Libraries; Malignant Neoplasms; Mannose; Membrane; Methodology; Methods; Nanostructures; Neurodegenerative Disorders; Pancreas; Peptides; Polymers; Polysaccharides; Process; Property; RNA Interference; Reagent; Research; Route; Serum; Small Interfering RNA; Structure; Surface; System; Technology; Testing; Therapeutic; Toxic effect; Transfection; base; biomaterial compatibility; cancer genetics; cancer therapy; cell assembly; cell type; clinical application; clinically relevant; design; gel electrophoresis; gene therapy; improved; in vivo; insight; knock-down; protein expression; public health relevance; research study; screening; self assembly; targeted delivery; uptake; vector

 DESCRIPTION (provided by applicant): RNA interference (RNAi) represents a platform of tremendous potential in the field of gene therapy. For therapeutics, a specific small interfering RNA (siRNA) is delivered into cells for the selective knock down of the encoded protein's expression. However, to fully realize the potential of siRNA therapeutics, safe and efficient delivery reagents must be developed. Recently in the Guan lab we have developed a dendritic peptide terminated bolaamphiphile system that can successfully deliver siRNA and knockdown protein expression. However, to increase clinical applications of the peptide bolaamphiphile, we must increase serum stability, biocompatibility, and systemic delivery. To address these issues I propose to synthesize a library of saccharide-functionalized bolaamphiphiles. Saccharide functionalization will increase serum stability by shielding the positive surface charge of the siRNA-polymer assembly, increase biocompatibility through reducing the membrane disruption by free amines, and finally will increase systemic delivery through lectin-saccharide interactions. I will fully investigate the self-assembly, biocompatibility, knockdown, and efficacy of this syste using similar methods developed in our lab to test related peptide bolaamphiphile system. Initial studies completed by myself have allowed for the creation of a mannose-functionalized bola amphiphile that has shown promising activity (88% knockdown of the target gene in serum). Successful completion of the proposed study will result in a new highly efficient siRNA delivery system, enabling further in vivo studies with collaborators which could lead to the successful treatment of several diseases including cancers, neurodegenerative disorders, and diabetes.

 描述（通过应用程序提出）：RNA干扰（RNAI）ICS，将特定的小干扰RNA（siRNA）传递到细胞中，以选择性地敲低编码的蛋白质的表达，但是，必须使用siRNA疗法的潜力，安全有效的递送试剂E开发了一种终止的树突状bola骨系统，可以成功地递送Sircdown Protetein Express siRNA-聚合物组装的正表电荷，增加生物相容性的自由胺破坏膜破坏，最后会增加全身性GH凝集素 - 六核的相互作用。 我将在实验室中完全研究该系统的自组装，敲低和效力，以测试相关的肽Bolaamphiphile系统siRNA递送系统，可以与合作者进行进一步的体内研究，这可能导致成功治疗严重性疾病，包括癌症，神经退行性疾病和糖尿病。