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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（由申请人提供）：尽管早期结直肠癌 (CRC) 患者的生存率已取得进展，但全身性转移（IV 期疾病）患者的生存率仅略有改善。目前的化疗药物虽然能够非常有效地杀死结直肠癌细胞，但受到其全身毒性的限制。如果要在癌症患者的生存方面取得进展，就需要高度创新的策略，将抗癌药物直接更有针对性地递送至结直肠癌转移灶。我们的最终转化目标是开发一种高效且毒性较小的方法，专门将抗癌药物递送至结直肠癌转移灶。为了实现这一目标，我们组建了一支多学科、高度协作的团队，他们处于结直肠癌分子信号传导途径、结直肠癌治疗方式、药物化学、新型纳米颗粒合成和递送系统的最前沿。在过去的两年里，我们在实现我们的目标方面取得了重大进展：(i) 使用新型三路连接 (3WJ) 基序，我们构建了热力学和化学稳定的三分支 RNA 纳米颗粒，其带有针对受体的适体，可以将小分子抑制剂或化疗剂特异性输送到肝脏中的 CRC 转移灶，(ii) 我们使用 pRNA-3WJ 基序作为支架，并在关键实验中证明，所得的 RNA 构建体保留了其折叠和独立功能，用于特定细胞结合、细胞进入和癌症靶向，在体外和体内，（iii）我们已经证明，RNA纳米颗粒在全身注射到小鼠体内后保持完整，并与肿瘤牢固结合，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良好的药理学特征，并且(iv)我们已经证明pRNA-3WJ能够在体内局部递送至CRC异种移植物和肝转移瘤。因此，我们提议的中心假设是，使用我们的 pRNA-3WJ 纳米粒子对 CRC 受体特异性递送化疗药物将为选择性靶向和抑制 CRC 转移提供安全、有效的策略。为了解决我们的假设，我们设计了具有以下具体目标的实验：1）构建与抗癌药物偶联的pRNA-3WJ纳米颗粒，并分析其体外稳定性、细胞摄取和抗增殖作用； 2) 确定pRNA-药物缀合物的体内药代动力学、稳定性、安全性和药物递送； 3)评估pRNA-3WJ纳米粒子与抗癌剂偶联的选择性递送和体内抗肿瘤效果。总之，我们对当前提案的热情不仅源于其固有的科学重要性，还源于其转化潜力、临床影响以及提供针对结直肠癌转移的更有效、毒性更低的输送系统的可能性。