Synergistic chemo-siRNA combination therapy

描述（由申请人提供）：siRNA癌症治疗剂的开发由于其在体内实体瘤中的不充分递送和转染而受到阻碍。这是由于其不利的物理化学性质、不稳定性和快速消除或截留在网状内皮系统（RES）中、溶酶体降解和毒性。这些问题中的一些可以通过RNA的结构修饰和通过使用“隐形”纳米载体来克服，所述纳米载体提高稳定性并降低RES截留和毒性。剩下的两个问题是不能到达位于血管远端的肿瘤细胞和不能实现足够的转染。我们已经获得了初步的结果，表明在聚乙二醇化的阳离子脂质载体中装载的化疗和siRNA的某些组合在携带几种类型的实体瘤的动物中产生了显著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siRNA治疗。预计拟议的研究将提高对体内实体瘤中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，而翻译研究将建立在这些信息的基础上，以开发最佳的化学siRNA治疗方案用于临床评估。 如果成功，这些研究将导致开发具有广泛应用的有效化学siRNA疗法。

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.