Tumor-targeted delivery of siRNA via sub-50 nanometer capsules

通过亚 50 纳米胶囊靶向肿瘤递送 siRNA

• 批准号: 7052244
• 负责人: GRETCHEN M UNGER
• 金额: $ 9.97万
• 依托单位: GENESEGUES, INC.
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-22 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7052244
• 关键词: birth; model; neoplasm /cancer; proteins

DESCRIPTION (provided by applicant): The prospect of using siRNAs as potent inhibitors to any gene of choice may provide a new therapeutic approach for many intractable diseases. However, a major impediment to successful development of siRNA-based therapies has been the general inability to deliver siRNA into cells in a stable and cell-specific manner in vivo using clinically relevant methods. GeneSegues has developed a novel delivery technology, sub-50 nanometer (s50) capsules, capable of efficient intracellular delivery of large molecule drugs to target tissues and cells. This is achieved by compressing large molecule drugs in sub-50 nm capsule shells formed entirely of protein or peptide ligands, to take advantage of receptor-mediated caveolar endocytosis for highly efficient transport across the cell membrane to intracellular compartments. In our pilot studies, we demonstrate effective delivery of nanoencapsulated siRNA against B-galactosidase to B-galcatosidase-(+) tumors at low dosing levels in mice. To build upon these promising early findings, our first aim in this proposed research entails assessing and optimizing siRNA nanocapsule formulations, including 1) developing and characterizing siRNA nanocapsule formulations for tumor-targeting by adapting results from successful research with conventional oligos, 2) comparing nanocapsule delivery to liposomal delivery in vitro, and 3) comparing nanocapsule delivery to naked delivery of modified-backbone siRNA in vivo using a model system. In a second aim focusing on therapeutic efficacy, we propose to compare nanocapsule delivery vs. naked delivery of modified-backbone siRNA against Casein Kinase 2, a recently validated cancer target, using an orthotopic xenograft model of human prostate cancer in nude mice. If successful, we expect that completion of this body of work would provide a solid framework for partnering with NIH and/or drug developers to progress encapsulated siRNA therapies forward. Manipulation of disease pathology at the gene level can lead to a cure, not just symptomatic treatment. Consequently, quality of life and survival of patients diagnosed with advanced disease would be expected to improve significantly with targeted siRNA therapeutics. The critical path to bringing siRNA therapeutics to market is effective drug delivery; potentially, this research will drive significant progress along that path.

描述（由申请人提供）：使用 siRNA 作为任何所选基因的有效抑制剂的前景可能为许多疑难疾病提供新的治疗方法。然而，成功开发基于 siRNA 的疗法的一个主要障碍是通常无法使用临床相关方法在体内以稳定且细胞特异性的方式将 siRNA 递送到细胞中。 GeneSegues 开发了一种新型递送技术，即亚 50 纳米 (s50) 胶囊，能够在细胞内有效地将大分子药物递送至目标组织和细胞。这是通过将大分子药物压缩在完全由蛋白质或肽配体形成的亚 50 nm 胶囊壳中来实现的，以利用受体介导的胞穴内吞作用，高效地穿过细胞膜运输到细胞内区室。在我们的初步研究中，我们证明了针对 B-半乳糖苷酶的纳米封装 siRNA 在小鼠体内以低剂量水平有效递送至 B-半乳糖苷酶-(+) 肿瘤。为了建立在这些有希望的早期发现的基础上，我们在这项拟议研究中的首要目标是评估和优化 siRNA 纳米胶囊制剂，包括 1) 通过采用传统寡核苷酸的成功研究结果来开发和表征用于肿瘤靶向的 siRNA 纳米胶囊制剂，2) 比较纳米胶囊递送与体外脂质体递送，以及 3) 比较纳米胶囊递送与修饰骨架的裸递送 使用模型系统进行体内 siRNA。第二个目标侧重于治疗效果，我们建议使用裸鼠中人类前列腺癌的原位异种移植模型，比较针对酪蛋白激酶 2（最近验证的癌症靶点）的修饰骨架 siRNA 的纳米胶囊递送与裸递送。如果成功，我们预计这项工作的完成将为与 NIH 和/或药物开发商合作提供坚实的框架，以推进封装的 siRNA 疗法的发展。在基因水平上操纵疾病病理可以治愈疾病，而不仅仅是对症治疗。因此，通过靶向 siRNA 治疗，被诊断患有晚期疾病的患者的生活质量和生存率有望显着改善。将 siRNA 疗法推向市场的关键途径是有效的药物输送；这项研究有可能将推动这条道路取得重大进展。