Use of nanogels to target delivery of siRNA to cancer cells in mice

描述(申请人提供)：卵巢癌是妇科癌症的主要死因。尽管肿瘤对手术切除和化疗的初始反应率高达80%，但大多数晚期卵巢癌女性最终会发展为耐药疾病。由于二线化疗药物的有效率只有15%-25%，显然有必要开发更好的治疗策略。小干扰RNA(SiRNAs)是一类先前被证明能高效灭活在培养的癌细胞中致癌基因(癌基因)的RNA分子。然而，由于siRNAs在生理条件下极不稳定的事实，阻碍了siRNAs作为临床重要治疗药物的发展。此外，目前还没有有效的方法来将这些潜在的治疗性分子靶向癌细胞。我们最近已经证明，被称为纳米凝胶的胶状纳米颗粒可以很容易地负载siRNA，并有针对性地将其潜在的治疗有效载荷输送到培养中生长的卵巢癌细胞。纳米凝胶保护siRNA分子不被降解，直到释放到癌细胞中。拟议的研究试图证明，这些无毒的纳米凝胶也可以用来有效地将siRNA靶向活体(实验小鼠)中的癌细胞。这些研究是将这项技术用于治疗人类癌症的潜在临床应用的先决条件。具体地说，针对EGFR(表皮生长因子受体)基因的siRNAs将被装载到专门针对卵巢癌细胞表面表达的蛋白质的纳米凝胶中。EGFR基因在卵巢和大多数其他类型的癌细胞中高度表达，已知可诱导细胞快速分裂，并对最常用的化疗药物产生抗药性。因此，肿瘤细胞中EGFR的失活具有重要的治疗价值。证明纳米凝胶可以有效地将治疗性siRNA输送到小鼠的癌细胞中，这将为这一令人兴奋的临床应用新技术的开发打开大门。 与公共卫生相关：能够提供针对特定针对癌细胞的癌基因的siRNA将是癌症治疗的主要贡献。开发一种小鼠模型来演示和改进这种靶向传递纳米技术是将该技术应用于临床的关键一步。

DESCRIPTION (provided by applicant): Ovarian cancer is the leading cause of death from gynecologic cancer. Despite high initial tumor response rates of 80% to surgical debulking and chemotherapy, most women with advanced ovarian cancer will eventually develop drug-resistant disease. Because second-line chemotherapeutic agents provide a response rate of only 15-25%, there is clearly a need to develop better therapeutic strategies. Small interfering RNAs (siRNAs) are a class of RNA molecules that previously have been demonstrated to be highly effective in inactivating cancer-causing genes (oncogenes) in cancer cells grown in culture. However, the development of siRNAs as clinically significant therapeutic agents has been hampered by the fact that siRNAs are extremely unstable at physiological conditions. In addition, there has been no effective way to target these potentially therapeutic molecules specifically to cancer cells. We have recently demonstrated that gelatinous-like nanoparticles called nanogels can be easily loaded with siRNAs and targeted to deliver their potentially therapeutic payload to ovarian cancer cells grown in culture. Nanogels protect the siRNA molecules from degradation until released into the cancer cells. The proposed studies seek to demonstrate that these non-toxic nanogels can be used to effectively target siRNAs to cancer cells in living organisms (experimental mice) as well. Such studies are pre-requisite to the potential clinical application of the technology for the treatment of cancer in humans. Specifically, siRNAs directed against the EGFR (epidermal growth factor receptor) gene will be loaded into nanogels engineered to specifically target proteins expressed on the surface of ovarian cancer cells. The EGFR gene is highly expressed in ovarian and most other types of cancer cells and is known to induce cells to rapidly divide and become resistant to most commonly used chemotherapy agents. Thus, the inactivation of EGFR in cancer cells has great therapeutic value. Demonstration that nanogels can be an effective vehicle for the delivery of therapeutic siRNAs to cancer cells in mice will open the door to the development of this exciting new technology of clinical application in humans. PUBLIC HEALTH RELEVANCE: The ability to deliver siRNA against oncogenes specifically targeted to cancer cells will be a major contribution to the treatment of cancer. Development of a mouse model in which to demonstrate and refine this targeted delivery nanotechnology is a key step in moving the technology into clinical practice.