Nanoformulations for siRNA Delivery to Ovarian Cancer

用于卵巢癌 siRNA 递送的纳米制剂

• 批准号: 7983674
• 负责人: Phillip A Sharp
• 金额: $ 26.9万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7983674
• 关键词: Antibodies; Binding Proteins; Biocompatible Materials; Cancer cell line; Cell Death; Cells; Cessation of life; Chemicals; Clinical Treatment; Collaborations; Cytoplasm; Cytosol; Development; Dose; Drug Kinetics; Electromagnetics; Gene Expression; Gene Silencing; Genes; Goals; Greater sac of peritoneum; Gynecologic; Human; Image; Immunodeficient Mouse; Laboratories; Ligands; Link; Lipids; Malignant Neoplasms; Malignant neoplasm of ovary; Membrane; Messenger RNA; Methods; Modeling; Modification; Mus; Nanotechnology; Normal Cell; Normal tissue morphology; Oncogenes; Ovarian; Pathway interactions; Peptide aptamers; Pharmacologic Substance; Polymers; Predisposition; Property; Proteins; RNA Interference; Research; Research Personnel; Serum; Small Interfering RNA; Specificity; Suppressor Genes; Surface; Survival Rate; Testing; The Sun; Therapeutic; Therapeutic Agents; Treatment Efficacy; aptamer; cancer cell; cancer diagnosis; cancer therapy; chemotherapeutic agent; design; efficacy testing; improved; in vivo; meetings; mouse model; multidisciplinary; nanoformulation; nanomaterials; nanoparticle; neoplastic cell; novel; nuclease; ovarian neoplasm; receptor; response; small molecule; success; targeted delivery; tumor; tumor growth

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.

几乎所有的癌症疗法都受到其精确地将致死剂量的治疗剂递送到肿瘤细胞同时保留正常组织的能力的限制。纳米技术的最新进展已经产生了具有显著生物学和材料特性的纳米材料，这些纳米材料可以用于增强癌症诊断和治疗。这些包括通过将纳米颗粒引导至肿瘤微环境中的受体的配体靶向肿瘤，提供用于成像和感测肿瘤的电磁特性，以及将化疗剂递送至体内肿瘤细胞。RNA干扰提供了一种有吸引力的手段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“不可用药”的基因子集。然而，siRNA的全身递送由于其小尺寸导致的药代动力学性质、将这些试剂递送到靶细胞的胞质溶胶中的要求以及其对血清核酸酶的敏感性而具有挑战性。迄今为止，用于递送siRNA的方法主要集中于化学修饰、使用聚合物、抗体、适体和肽的载体开发，成功有限。该项目的目标是组建一个多学科团队， 通过递送治疗性siRNA来管理卵巢癌。作为最致命的妇科恶性肿瘤，五年生存率为31%，迫切需要新的治疗方法。这种恶性肿瘤在腹膜腔中扩散，向该腔室输送治疗剂可延长生存期。 siRNA可以被设计为沉默大多数基因，如果不是所有基因的话，因此可以用于阻断与正常细胞相比诱导癌细胞死亡的途径。我们建议继续开发和测试用于递送siRNA治疗卵巢癌的纳米颗粒。具体目标是：1通过纳米颗粒递送siRNA至特定基因的鉴定和测试，当沉默时诱导腹膜腔中卵巢癌细胞亚群的细胞死亡，2开发将siRNA靶向递送至卵巢肿瘤的模块化纳米材料，3开发由新型生物材料组成的安全有效的纳米颗粒，以将siRNA递送至腹膜腔中的卵巢癌细胞。