Synergistic chemo-siRNA combination therapy

协同化疗-siRNA联合疗法

• 批准号: 8513941
• 负责人: Jessie L.-S. Au
• 金额: $ 35.01万
• 依托单位: OPTIMUM THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-26 至 2016-07-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8513941
• 关键词: Affect; Animals; Apoptosis; Blood Vessels; Caliber; Cancer Patient; Cells; Chemosensitization; Cisplatin; Clinical; Combination Drug Therapy; Combined Modality Therapy; Data; Development; Distal; Dose; Double-Stranded RNA; Drug Kinetics; Endocytosis; Endosomes; Failure; Gene Proteins; Genes; Genetic Structures; Goals; Immunocompetent; Implant; In Vitro; Injection of therapeutic agent; Intravenous; Kinetics; Lead; Lipids; Liposomes; Lysosomes; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of ovary; Malignant neoplasm of pancreas; Measures; Mediating; Messenger RNA; Modeling; Modification; Molecular; Mus; Normal Cell; Nucleotides; Paclitaxel; Patients; Peritoneal; Pharmacodynamics; Property; Proteins; RNA; RNA Interference; Radiation; Regimen; Resistance; Reticuloendothelial System; Small Interfering RNA; Solid Neoplasm; Spatial Distribution; Stretching; Therapeutic; Time; Toxic effect; Transfection; Translating; Translations; Treatment Protocols; Tumor-Derived; Up-Regulation; Work; cancer type; chemotherapy; cytotoxicity; density; improved; in vivo; intraperitoneal; malignant breast neoplasm; nanocarrier; nanoparticle; neoplastic cell; novel; outcome forecast; pancreatic neoplasm; pre-clinical; research clinical testing; residence; selective expression; subcutaneous; survivin; translational study; tumor; tumor xenograft; uptake

DESCRIPTION (provided by applicant): The development of siRNA cancer therapeutics has been impeded by its inadequate delivery and transfection in solid tumors in vivo. This is due to their unfavorable physicochemical properties, instability and rapid elimination or entrapment in the reticuloendothelial system (RES), lysosomal degradation, and toxicity. Some of these problems can be overcome by structural modifications of RNA and by using "stealth" nano carriers that improve the stability and reduce the RES-entrapment and toxicity. The two remaining problems are the inability to reach tumor cells located distal to blood vessels and the inability to achieve sufficient transfection. We have obtained preliminary results indicating that certain combinations of chemotherapy and siRNA loaded in a pegylated cationic lipid carrier yielded significant target protein knockdown and therapeutic synergy in animals bearing several types of solid tumors. The goals of this project are to determine the mechanisms of in vivo synergy and to translate these findings into potentially useful chemo-siRNA therapy. The proposed studies are expected to improve the understanding of the barriers to siRNA delivery and transfection in solid tumors in vivo and indicate paths to overcome these major impediments, while translational studies will build on this information to develop optimal chemo-siRNA therapy regimens for clinical evaluation. If successful, the studies will lead to the development of effective chemo-siRNA therapies with broad applications.

描述(申请人提供)：由于siRNA在体内实体瘤中的传递和转染不充分，阻碍了siRNA癌症治疗的发展。这是由于其不良的物理化学性质、不稳定性和在网状内皮系统(RES)中的快速消除或包裹、溶酶体降解和毒性所致。其中一些问题可以通过修改RNA的结构和使用“隐形”纳米载体来克服，这些载体可以提高稳定性，减少再包裹和毒性。剩下的两个问题是无法到达血管远端的肿瘤细胞，以及无法实现足够的转基因。我们已经获得的初步结果表明，某些组合的化疗和聚乙二醇化阳离子脂质载体中的siRNA在几种类型的实体瘤动物身上产生了显着的靶蛋白击倒和治疗协同作用。该项目的目标是确定体内协同作用的机制，并将这些发现转化为潜在有用的化学siRNA疗法。拟议的研究有望提高对体内实体瘤中siRNA传递和转基因障碍的理解，并指明克服这些主要障碍的途径，而翻译研究将基于这些信息来开发用于临床评估的最佳化学-siRNA治疗方案。如果成功，这些研究将导致有效的化学-siRNA疗法的开发，具有广泛的应用。