Nanoformulations for siRNA Delivery to Ovarian Cancer

几乎所有的癌症治疗都受到限制，因为它们无法准确地将致命剂量的治疗剂输送到肿瘤细胞，同时又能保留正常组织。纳米技术的最新进展产生了具有显著生物学和材料特性的纳米材料，可用于加强癌症诊断和治疗。这些措施包括通过将纳米颗粒定向到肿瘤微环境中的受体的配体来靶向肿瘤，为成像和传感肿瘤提供电磁特性，以及在体内向肿瘤细胞输送化疗药物。RNA干扰提供了一种诱人的方法来沉默具有非凡特异性的基因的表达，特别是对于被认为是“不能用药”的基因子集。然而，siRNAs的系统递送一直是具有挑战性的，因为它们的小尺寸导致药代动力学特性，这些药物需要递送到靶细胞的胞浆中，以及它们对血清核酸酶的敏感性。到目前为止，传递siRNAs的方法主要集中在化学修饰、利用聚合物、抗体、适配子和多肽开发载体，但收效甚微。该项目的目标是组建一个多学科团队，以提高 通过传递治疗性siRNA来治疗卵巢癌。作为最致命的妇科恶性肿瘤，5年生存率为31%，迫切需要新的治疗方法。这种恶性肿瘤在腹膜腔内扩散，向该腔内输送治疗药物可延长存活期。 与正常细胞相比，siRNAs可以被设计成沉默大多数(如果不是全部)基因，从而可以用来阻断导致癌细胞死亡的途径。我们建议继续开发和测试纳米颗粒，用于传递siRNAs来治疗卵巢癌。其具体目标是：1通过纳米颗粒递送特定基因的siRNAs来鉴定和测试当沉默时导致腹膜腔内卵巢癌细胞亚群细胞死亡的siRNAs；2开发靶向卵巢肿瘤的模块化纳米材料；3开发安全有效的纳米颗粒，由新型生物材料组成的纳米颗粒将siRNA递送到腹膜腔内的卵巢癌细胞。

Nearly all cancer therapies are limited by their ability to precisely deliver a lethal dose of a therapeutic agent to tumor cells while sparing normal tissue. Recent progress in nanotechnology has resulted in nanomaterials with remarkable biological and material properties that can be leveraged for enhanced cancer diagnosis and therapy. These include targeting of tumors via ligands that direct nanoparticles to receptors in the tumor microenvironment, providing electromagnetic properties for imaging and sensing tumors, and delivery chemotherapeutic agents to tumor cells in vivo. RNA interference offers an attractive means to silence expression of genes with extraordinary specificity, particularly for the subset of genes considered "undruggable". However, systemic delivery of siRNAs has been challenging due to pharmacokinetic properties resulting from their small size, the requirement for delivery of these agents into the cytosol of target cells, and their susceptibility to serum nucleases. To date, approaches for delivery of siRNAs have primarily focused on chemical modifications, carrier development using polymers, antibodies, aptamers, and peptides with limited success. The goal of this project is to assemble a multidisciplinary team to improve the management of ovarian cancer by delivering therapeutic siRNAs. As the most lethal gynecologic malignancy with 31% five-year survival rates, new therapies are desperately needed. This malignancy disseminates in the peritoneal cavity and delivery of therapeutic agents to this compartment has shown to prolong survival. siRNAs can be designed to silence most, if not all genes and thus could be used to block pathways that induce cell death in cancer cells as compared to normal cells. We propose to continue the development and testing of nanoparticles for the delivery of siRNAs to treat ovarian cancer. The specific aims are: 1 Identification and testing by nanoparticle delivery of siRNAs to specific genes that when silenced induce cell death of subsets of ovarian cancer cells in the peritoneal cavity, 2 Development of modular nanomaterials that will target the delivery of siRNAs to ovarian tumors and 3 Development of safe and effective nanoparticles composed of novel biomaterials to deliver siRNA to ovarian cancer cells in the peritoneal cavity.