Spatiotemporal delivery of synergistic drug combinations to kidney cancer

肾癌协同药物组合的时空递送

基本信息

批准号：
10238802
负责人：
Venkata Sabbisetti
金额：
$ 37.82万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10238802
关键词：
Address Adverse effects Affinity Animals Antibodies Binding Biocompatible Materials Biodistribution Biological Biology Biometry Blood Circulation Blood Vessels Caring Cell Death Cell Line Chemistry Clinical Combined Modality Therapy Computer-Aided Design Critical Pathways Development Disease Dose Dose-Limiting Drug Combinations Drug Formulations Drug Kinetics Drug Targeting Drug or chemical Tissue Distribution Drug resistance Engineering Epithelial Evaluation Exhibits Experimental Designs FRAP1 gene Foundations Goals Half-Life Home Homing Human Hybridomas Hydrophobicity Immune In Vitro KDR gene Lateral Ligands Malignant Epithelial Cell Malignant Neoplasms Maximum Tolerated Dose Mechanics Metastatic Renal Cell Cancer Modality Modeling Molecular Morbidity - disease rate Morphology Mus Nature Neoplasm Metastasis Nephrology Normal tissue morphology Outcome Pathology Pathway interactions Patients Performance Pharmaceutical Preparations Pharmacologic Substance Positioning Attribute Prodrugs Property Radiation Rattus Refractory Renal Cell Carcinoma Renal carcinoma Reporting Resistance Resistance development Signal Pathway Signal Transduction Surface System TNFSF15 gene Technology Testing Therapeutic Therapeutic Index Tissues Toxic effect Treatment Efficacy Treatment-related toxicity Tubular formation Tumor Tissue Vascular Endothelial Growth Factors Work Xenograft Model base clinical translation cytokine cytokine therapy density design effective therapy experience head-to-head comparison improved in vivo inhibitor/antagonist mortality mouse model multimodality nano nanoassembly nanocarrier nanoformulation nanomedicine nanoparticle nanoparticle delivery neoplastic cell novel novel therapeutic intervention prevent quantum rat KIM-1 protein simulation spatiotemporal success targeted agent targeted delivery targeted treatment therapy outcome therapy resistant treatment response tumor tumor heterogeneity

项目摘要

Metastatic renal cell carcinoma (RCC) is a devastating disease often refractory to radiation, chemo, and cytokine therapy. Agents targeting the VEGF and mTOR pathways remain the foundation of RCC treatment. Despite marginal improvement in survival with targeted therapy, major limitations exist mainly because of the inter and intra-tumor heterogeneity and redundant pathway activation. While some patients with RCC are inherently refractory to therapy, others who initially respond to single or sequential targeted therapy eventually progress. Efforts to extend the clinical benefit of these agents with combination therapy have resulted in prohibitive toxicity, often with no overall benefit. Targeted multimodality nanoparticles hold great promise in this scenario; however, such modalities for RCC treatment are not currently available. Our goal is to engineer a targeted nanoparticle with clinically validated biomaterials and rationally modified drugs, which will self assemble into a nano-carrier system and provide exquisite spatiotemporal control over drug release to enhance the therapeutic efficacy and reduce off-target toxicity. Our specific aims are the following: Aim 1: Engineer and characterize dual drug-loaded targeted high-efficiency nanoparticles for RCC. Because of the small size and high hydrophobicity, targeted drugs for PI3K and VEGF often exhibit suboptimal pharmacokinetics with a large volume of distribution, and tend to accumulate in healthy tissues causing off target toxicity. Further, traditional pharmaceutical approaches for nano-formulation have been challenge with these molecules because of their incompatible physicochemical properties. We hypothesize that this can be addressed by rationally re-engineering the active agents into pro-drug amphiphiles that facilitate supramolecular nano-assembly into stable high efficiency nanoparticles. We will decorate the SNPs with a targeting ligand for better homing and improved potency. Further, we will optimize conjugation chemistry and ligand density on the SNPs. Aim 2: Pharmacokinetic, bio-distribution and toxicity evaluation of the targeted high-efficiency nanoparticles. In this aim, we will test our hypothesis that targeted SNPs are safe and will preferentially accumulate in tumor tissues yielding high therapeutic index. Aim 3: A mechanistic ananlysis of in vivo efficacy of the high-efficiency nanoparticles in RCC. We hypothesize that mechanistically inspired and surface functionalized nanoparticles that deliver payloads directly to tumor cells and inhibits PI3K-mTORC1/2 and MET/VEGFR2/Tie-2 signaling will regress RCC, evade tumor resistance, and thus improve antitumor outcome with reduced adverse effects. We will test this hypothesis on an array of RCC cell lines and biologically relevant experimental mouse models. We will also perform a head-to-head comparison of targeted vs. untargeted SNPs for their therapeutic efficacy and toxicity. We will dissect the performance of SNPs at the animal (survival, tumor regression), tissue (bio-distribution, toxicity), and molecular (activity of various signaling pathways) levels. We believe that our findings can significantly contribute to the development of novel therapeutic approaches and in the advancement of management strategies in renal cell carcinoma and help reduce associated mortality and morbidity.

转移性肾细胞癌（RCC）是一种毁灭性疾病，通常对辐射，化学疗法和细胞因子疗法。针对VEGF和MTOR途径的代理仍然是RCC治疗的基础。尽管有针对性疗法的生存率很小，但主要局限性主要是因为肿瘤内和肿瘤内异质性和冗余途径激活。虽然有些RCC患者是天生对治疗的难治性，最初对单一或顺序靶向治疗做出反应的其他人进步。通过组合疗法扩大这些药物的临床益处的努力已导致过度的毒性，通常没有总体好处。有针对性的多模式纳米颗粒在这种情况；但是，目前尚不可用的RCC治疗方式。我们的目标是设计具有临床验证的生物材料和合理修饰的药物的靶向纳米颗粒，这将自我组装成纳米载体系统，并对药物释放提供精致的时空控制增强治疗功效并降低脱靶毒性。我们的具体目的是：目标1：工程师并表征了RCC的双重靶向高效纳米颗粒。因为小型和高疏水性，PI3K和VEGF的靶向药物经常表现出次优具有大量分布的药代动力学，并且倾向于在健康组织中积聚靶毒性。此外，传统的纳米形成药物方法一直是挑战这些分子由于其不兼容的物理化学特性。我们假设这可能是通过合理地将活性代理重新设计为促进毒品的两亲物超分子纳米组装成稳定的高效率纳米颗粒。我们将用靶向配体以更好地归巢和提高效力。此外，我们将优化结合化学和 SNP上的配体密度。目标2：药代动力学，生物分布和毒性评估靶向高效纳米颗粒。在此目标中，我们将检验我们的假设，即目标SNP是安全的并优先积聚在产生高治疗指数的肿瘤组织中。目标3：机械 RCC中高效率纳米颗粒的体内功效的anan透析。我们假设这一点机械启发和表面功能化的纳米颗粒，这些纳米颗粒将有效载荷直接传递到肿瘤细胞并抑制PI3K-MTORC1/2和MET/VEGFR2/TIE-2信号传导将回归RCC，逃避肿瘤耐药性，从而通过减少不良反应来改善抗肿瘤结果。我们将在数组上检验此假设 RCC细胞系和生物学相关的实验小鼠模型。我们还将表演对靶向性SNP的治疗功效和毒性的比较。我们将剖析 SNP在动物（生存，肿瘤消退），组织（生物分布，毒性）和分子（各种信号通路的活性）水平。我们相信我们的发现可以显着有助于发展新型治疗方法和管理的发展肾细胞癌的策略，有助于降低相关的死亡率和发病率。