Synergistic chemo-siRNA combination therapy

协同化疗-siRNA联合疗法

基本信息

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
项目类别：
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

项目摘要

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癌症疗法的发展因其在实体瘤体内的递送和转染不足而受到阻碍。这是由于它们不利的理化性质、不稳定性以及网状内皮系统 (RES) 中的快速消除或截留、溶酶体降解和毒性。其中一些问题可以通过 RNA 的结构修饰和使用“隐形”纳米载体来克服，从而提高稳定性并减少 RES 截留和毒性。剩下的两个问题是无法到达位于血管远端的肿瘤细胞以及无法实现足够的转染。我们获得的初步结果表明，化疗和装载在聚乙二醇化阳离子脂质载体中的 siRNA 的某些组合在患有几种类型实体瘤的动物中产生了显着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疗 siRNA 疗法。拟议的研究预计将提高对实体瘤体内 siRNA 递送和转染障碍的理解，并指出克服这些主要障碍的途径，而转化研究将在此信息的基础上开发用于临床评估的最佳化疗 siRNA 治疗方案。如果成功，这些研究将导致开发出具有广泛应用的有效化疗 siRNA 疗法。