Mesenchymal Stem Cell-Based Targeted Combined Therapy for Pancreatic Ductal Adenocarcinoma

基于间充质干细胞的胰腺导管腺癌靶向联合治疗

基本信息

批准号：
10666700
负责人：
Buddhadev Layek
金额：
$ 22.63万
依托单位：
NORTH DAKOTA STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-03-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10666700
关键词：
Acute Affect Antineoplastic Agents Apoptosis Autopsy Behavior Biodistribution Biomedical Engineering Cells Charge Clinical Combined Modality Therapy Cytotoxic agent Desmoplastic Diagnostic Dose Dose Limiting Drug Delivery Systems Drug Kinetics Drug Targeting Drug resistance Encapsulated Ensure Formulation Goals Growth HDAC10 gene Hematology Histone Deacetylase Histone Deacetylase Inhibitor Histopathology Home Human In Vitro Literature Malignant Neoplasms Malignant neoplasm of pancreas Maximum Tolerated Dose Mediating Mesenchymal Stem Cells Modality Mus Neurologic Normal tissue morphology Organ Outcomes Research Pancreas Pancreatic Ductal Adenocarcinoma Particle Size Pathway interactions Pharmaceutical Preparations Phenotype Play Protocols documentation Regimen Research Resistance Role Solid Neoplasm Surface Survival Rate System Testing Therapeutic Therapeutic Agents Time Tissues Toxic effect Treatment Efficacy Treatment outcome Treatment-related toxicity Tumor Tissue Work acute toxicity anticancer treatment cancer therapy cell killing chemotherapeutic agent chemotherapy cytotoxic drug release kinetics effectiveness evaluation improved in vitro Model mouse model nanocarrier nanoengineering nanoparticle nanoparticle delivery nanopolymer nanotoxicity neoplastic cell novel novel strategies novel therapeutics oxaliplatin pancreatic ductal adenocarcinoma cell pancreatic ductal adenocarcinoma model pancreatic neoplasm patient subsets pre-clinical research small molecule success targeted delivery targeted treatment tumor tumor growth

项目摘要

PROJECT SUMMARY Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human malignancies, with a five-year survival rate of 10.8%. Lack of efficient strategies to achieve cytotoxic concentrations of chemotherapeutics in the tumor tissue and the tumor's innate resistance to chemotherapy are the significant barriers in improving treatment outcomes for PDAC. Thus, new approaches for tumor-selective delivery of chemotherapeutics can enhance the therapeutic efficacy while minimizing chemotherapy-associated toxicities. Unfortunately, current nanocarrier systems primarily rely on the inefficient passive accumulation in the tumor. Here we propose a new approach for treating PDAC with a combination of a novel histone deacetylase (HDAC) inhibitor, entinostat, and a leading chemotherapeutic agent, oxaliplatin, at their synergistic ratio. The proposed studies will evaluate nanoengineered MSC as a drug delivery platform to selectively accumulate cytotoxic agents in pancreatic tumors. Based on the existing literature and our preliminary findings, we hypothesize that MSCs-mediated tumor- targeted delivery of oxaliplatin and entinostat at their synergistic ratio would significantly reduce pancreatic tumor growth and enhance the efficacy without acute toxicity. To test our hypothesis, we propose the following Aims. Aim 1: Formulate drug-loaded nano-MSCs and determine their cellular efficacy. Our preliminary studies demonstrate a dose-dependent synergistic therapeutic interaction between free oxaliplatin and entinostat in an in vitro model of PDAC. We will encapsulate oxaliplatin and entinostat separately in the surface-functionalized polymeric nanoparticles. Nanoparticles will be characterized for their particle size, surface charge, drug loading, and in vitro drug release. The time- and dose-dependent drug loading capacity of MSCs and drug release rate and mechanism from nanoengineered MSCs will also be evaluated. Also, both nanoparticle formulation and nanoengineering protocols will be optimized to improve the drug loading capacity of MSCs without affecting their native phenotype, viability, or migratory behavior. Finally, we will determine the synergistic ratio of entinostat and oxaliplatin-loaded MSCs to kill PDAC cells. Based on our preliminary results, the working hypothesis for this Aim is that the nanoengineered MSCs will enable sustained release of oxaliplatin without introducing resistance, ensuring enhanced tumor cell killing. Aim 2: Evaluate the effectiveness of nano-MSCs using an orthotopic mouse model of PDAC. First, we will determine the maximum tolerated dose (MTD), pharmacokinetics, biodistribution, acute and subchronic toxicities of nanoengineered MSCs in an orthotopic mouse model of PDAC. Using this optimized dosing strategy, we will determine the therapeutic efficacy of oxaliplatin-loaded nanoengineered MSCs alone and combined with entinostat-loaded MSCs using an orthotopic mouse model of PDAC. We will conduct detailed histopathology of the pancreas and other vital organs in necropsy tumor-bearing mice.

项目概要胰腺导管腺癌（PDAC）是人类最致命的恶性肿瘤之一，五年内发病率成活率10.8%。缺乏有效的策略来达到化疗药物的细胞毒性浓度肿瘤组织和肿瘤对化疗的先天抵抗是改善的重要障碍 PDAC 的治疗结果。因此，肿瘤选择性递送化疗药物的新方法可以提高治疗效果，同时最大限度地减少化疗相关的毒性。不幸的是，目前纳米载体系统主要依赖于肿瘤中低效的被动积累。在这里我们提出一个新的联合使用新型组蛋白脱乙酰酶 (HDAC) 抑制剂、恩替司他 (entinostat) 和领先的化疗药物奥沙利铂的协同作用。拟议的研究将评估纳米工程 MSC 作为药物递送平台，选择性地在胰腺中积累细胞毒剂肿瘤。根据现有文献和我们的初步研究结果，我们假设 MSC 介导的肿瘤以协同比例靶向递送奥沙利铂和恩替司他将显着减少胰腺肿瘤生长增强药效且无急性毒性。为了检验我们的假设，我们提出以下目标。目标 1：配制载药纳米 MSC 并确定其细胞功效。我们的初步研究证明游离奥沙利铂和恩替司他之间存在剂量依赖性协同治疗相互作用 PDAC的体外模型。我们将奥沙利铂和恩替司他分别封装在表面功能化的聚合物纳米颗粒。纳米颗粒的特征在于其粒径、表面电荷、载药量、和体外药物释放。 MSCs 的时间和剂量依赖性载药能力和药物释放速率纳米工程间充质干细胞的作用机制也将得到评估。此外，纳米颗粒配方和纳米工程方案将被优化，以提高间充质干细胞的载药能力，而不影响其原生表型、生存力或迁移行为。最后，我们将确定恩替司他和恩替司他的协同比例负载奥沙利铂的 MSC 可杀死 PDAC 细胞。根据我们的初步结果，该目标的工作假设纳米工程 MSC 将能够持续释放奥沙利铂而不产生耐药性，确保增强肿瘤细胞杀伤力。目标 2：使用 PDAC 原位小鼠模型评估纳米 MSC 的有效性。首先，我们将确定最大耐受剂量 (MTD)、药代动力学、生物分布、急性和亚慢性毒性 PDAC 原位小鼠模型中纳米工程 MSC 的研究。使用这种优化的剂量策略，我们将确定负载奥沙利铂的纳米工程 MSC 单独和联合治疗的疗效使用 PDAC 原位小鼠模型加载恩替司他 (entinostat) 的 MSC。我们将进行详细的组织病理学检查尸检荷瘤小鼠的胰腺和其他重要器官。