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

基本信息

批准号：
9753735
负责人：
Bernard Mark Evers
金额：
$ 27.2万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-25 至 2020-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9753735
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 nanotechnology platform novel overexpression public health relevance receptor scaffold small molecule inhibitor systemic toxicity targeted delivery targeted treatment tumor uptake

项目摘要

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（由适用提供）：尽管在患有早期阶段结直肠癌（CRC）的患者的存活中取得了进展，但在全身转移（IV期疾病）的患者中仅注意到最小的改善。当前的化学治疗剂虽然在杀死CRC细胞方面非常有效，但受其全身毒性的限制。如果在癌症患者的存活中取得进步，则需要高度创新的策略才能直接将抗癌药物直接递送到CRC转移酶。我们的最终翻译目标是开发一种高效且毒性较小的方法，以将抗癌剂专门为CRC转移剂提供。 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 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 apatmer 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, 在体外和体内，（iii）我们都表明，全身注射到小鼠后，RNA纳米颗粒保持完整，并与正常器官或时机积聚的肿瘤强烈结合。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物特征，（iv）我们已经在PRNA-3WJ递送到CRC Xenographictic和肝转移中局部局部局部。这是我们提案的中心假设是，使用我们的PRNA-3WJ纳米颗粒的CRC受体特异性化学治疗剂递送将提供一种安全有效的策略，以选择性地靶向和抑制CRC转移。为了解决我们的假设，我们设计了以下特定目的的实验：1）构建PRNA-3WJ纳米颗粒与抗癌剂结合并分析其稳定性，细胞摄取和体外抗增殖作用； 2）确定体内PRNA-Crug con轭物的TE药代动力学，稳定性，安全性和药物递送； 3）评估PRNA-3WJ纳米颗粒的选择性递送和体内抗肿瘤效应与抗癌药物结合。总而言之，我们对当前建议的热情不仅是由于其固有的科学重要性所驱动的，而且还取决于其翻译潜力，临床影响以及提供针对CRC转移剂的更有效且毒性更低的输送系统的可能性。