Synergistic chemo-siRNA combination therapy

协同化疗-siRNA联合疗法

• 批准号: 8338813
• 负责人: Jessie L.-S. Au
• 金额: $ 37.25万
• 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/8338813
• 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（由申请人提供）：siRNA癌症治疗剂的发展受到其体内实体瘤的递送和转染的不足。这是由于它们不利的物理化学特性，不稳定性以及在网状内皮系统（RES），溶酶体降解和毒性中的快速消除或捕获。这些问题中的一些可以通过RNA的结构修饰和使用“隐身”纳米载体来克服，从而改善稳定性并减少重新安装和毒性。剩下的两个问题是无法到达位于血管远端的肿瘤细胞，并且无法实现足够的转染。我们已经获得了初步结果，表明在卵巢的阳离子脂质载体中加载的化学疗法和siRNA的某些组合产生了具有多种实体瘤的动物中明显的靶蛋白敲低和治疗协同作用。 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化学治疗。预计拟议的研究将提高对体内实体瘤siRNA递送和转染的障碍的理解，并指示克服这些主要障碍的途径，而翻译研究将基于此信息以开发最佳的化学化学疗法治疗方案进行临床评估。 如果成功，这些研究将导致开发具有广泛应用的有效化学化学疗法。