Novel pRNA Nanoparticle Delivery as Directed Therapy for Colorectal Cancer Metastasis

新型 pRNA 纳米颗粒递送作为结直肠癌转移的定向治疗

• 批准号: 9547788
• 负责人: Bernard Mark Evers
• 金额: $ 28.04万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-25 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9547788
• 关键词: Address; Antineoplastic Agents; Binding; Biodistribution; Biological Models; Cancer Cell Growth; Cancer Etiology; Cancer Patient; Cell Adhesion Molecules; Cell-Adhesion Molecule Receptors; Cells; Cessation of life; Chemicals; Clinical; Colorectal Cancer; Coupled; Disease; Distant; Drug Delivery Systems; Drug Kinetics; Early treatment; Epithelial Cells; Excision; FOLR1 gene; Goals; Growth; Human; In Vitro; Injections; Intestines; Kentucky; Laboratories; Liver; Malignant Neoplasms; Metastatic Neoplasm to the Liver; Modality; Molecular; Motor; Mucous Membrane; Mus; Nanotechnology; Neoplasm Metastasis; Organ; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Process; RNA; Research; Resistance; Safety; Signal Pathway; Submucosa; System; Technology; Thermodynamics; Tissues; Tumor Tissue; Universities; Xenograft procedure; antitumor effect; aptamer; base; cancer cell; cancer survival; chemotherapeutic agent; colorectal cancer metastasis; colorectal cancer treatment; design; experimental study; improved; in vivo; innovation; metastatic colorectal; mortality; multidisciplinary; nanoparticle; nanoparticle delivery; novel; overexpression; public health relevance; receptor; scaffold; small molecule inhibitor; systemic toxicity; targeted delivery; targeted treatment; tumor; uptake

 DESCRIPTION (provided by applicant): Although progress has been made in survival of patients with earlier stage colorectal cancer (CRC), only minimal improvement has been noted in patients with systemic metastases (Stage IV disease). Current chemotherapeutic agents, while highly effective at killing CRC cells, are limited by their systemic toxicity. If advances ar to be made in the survival of cancer patients, highly innovative strategies are required for more targeted delivery of anti-cancer agents directly to CRC metastases. Our ultimate translational goal is to develop a highly effective and less toxic approach to specifically deliver anti-cancer agents to CRC metastases. To achieve this goal, we have assembled a multidisciplinary and highly collaborative team who are at the forefront of molecular signaling pathways in CRC, CRC treatment modalities, medicinal chemistry, novel nanoparticle synthesis and delivery systems. Over the last two years, we have made significant progress to achieve our goals: (i) using a novel three-way junction (3WJ) motif, we have constructed thermodynamically and chemically stable three-branched RNA nanoparticles with an aptamer against receptors that can deliver a small molecule inhibitor or chemotherapeutic agent specifically to CRC metastases in the liver, (ii) we have constructed a variety of RNA nanoparticles using the pRNA-3WJ motif as a scaffold and have demonstrated in critical experiments that the resulting RNA constructs retained their folding and independent functionalities for specific cell binding, cell entry and cancer targeting, both in vitro and in vivo, (iii) we have shown that the RNA nanoparticles remain intact after systemic injection into mice and strongly bind to tumors with little accumulation in normal organs or tissues; these RNA constructs are non- toxic, non-immunogenic, and display favorable pharmacological profiles in mice, and (iv) we have demonstrated localized in vivo delivery of pRNA-3WJ to CRC xenografts and liver metastases. Thus, the central hypothesis of our proposal is that CRC receptor-specific delivery of chemotherapeutic agents using our pRNA-3WJ nanoparticles will provide a safe, effective strategy to selectively target and inhibit CRC metastasis. To address our hypothesis, we have designed experiments with the following Specific Aims: 1) to construct pRNA-3WJ nanoparticles coupled with anti-cancer agents and analyze their stability, cellular uptake and anti-proliferative effects in vitro; 2) to determine te pharmacokinetics, stability, safety and drug delivery of pRNA-drug conjugates in vivo; and 3) to evaluate the selective delivery and in vivo anti-tumor effect of pRNA- 3WJ nanoparticles coupled with anti-cancer agents. In summary, our enthusiasm for our current proposal is driven not only by its inherent scientific importance, but also by its translational potential, clinical impact, and the possibility to provide a more effective and less toxic delivery system targeting CRC metastases.

 描述（由申请人提供）：尽管早期结直肠癌（CRC）患者的生存率有所提高，但在全身转移（IV期疾病）患者中仅观察到极小的改善。目前的化学治疗剂虽然在杀死CRC细胞方面非常有效，但受到其全身毒性的限制。如果要在癌症患者的存活率方面取得进展，则需要高度创新的策略来更有针对性地将抗癌剂直接递送至CRC转移灶。我们的最终转化目标是开发一种高效且毒性较小的方法，以特异性地向CRC转移提供抗癌药物。为了实现这一目标，我们组建了一个多学科和高度协作的团队，他们处于CRC分子信号通路、CRC治疗方式、药物化学、新型纳米颗粒合成和递送系统的最前沿。在过去两年中，我们在实现目标方面取得了重大进展：（i）使用新的三向连接（3 WJ）基序，我们已经构建了具有针对受体的适体的药物学和化学稳定的三分支RNA纳米颗粒，所述适体可以将小分子抑制剂或化疗剂特异性递送至肝脏中的CRC转移，（ii）我们已经使用pRNA-3 WJ基序作为支架构建了各种RNA纳米颗粒，并且在关键实验中证明了所得RNA构建体保留了它们的折叠和用于特异性细胞结合、细胞进入和癌症靶向的独立功能， 在体外和体内，（iii）我们已经表明，RNA纳米颗粒在全身注射到小鼠中后保持完整，并且与肿瘤强烈结合，在正常器官或组织中几乎没有积累;这些RNA构建体是无毒的、非免疫原性的，并且在小鼠中显示出有利的药理学特性，和（iv）我们已经证明了pRNA-3 WJ向CRC异种移植物和肝转移瘤的局部体内递送。因此，我们建议的中心假设是使用我们的pRNA-3 WJ纳米颗粒的化疗剂的CRC受体特异性递送将提供选择性靶向和抑制CRC转移的安全、有效的策略。为了验证我们的假设，我们设计了具有以下特定目的的实验：1）构建与抗癌药物偶联的pRNA-3 WJ纳米颗粒，并分析其体外稳定性、细胞摄取和抗增殖作用; 2）测定pRNA-药物偶联物的体内药代动力学、稳定性、安全性和药物递送;以及3）评价偶联抗癌剂的pRNA-3 WJ纳米颗粒的选择性递送和体内抗肿瘤作用。总之，我们对当前提案的热情不仅是由于其固有的科学重要性，而且还由于其转化潜力，临床影响以及提供靶向CRC转移的更有效且毒性更低的递送系统的可能性。