Targeting Solid Tumors Using Nano-Engineered MSCs

项目摘要/摘要 缺乏有效的战略来实现抗癌药物的细胞毒性浓度在深层次和 转移性癌症一直是提高肺癌治疗结果的主要障碍。间充质 干细胞(MSCs)具有极强的肿瘤归巢能力，因此有可能选择性地 为肿瘤组织提供抗癌治疗。之前的一些研究表明，从基因上讲， 修饰后的MSCs可用于将抗癌肽和蛋白输送到肿瘤组织。然而，MSCs 到目前为止还没有被探索来传递小分子，可能是因为固定小分子的困难 分子在细胞中持续存在的时间。 本研究的总体目标是研究纳米工程间充质干细胞(Nano-MSC)的有效性。 在肺癌方面。我们假设，MSCs被设计成携带载药的聚合物纳米颗粒将允许 用于肿瘤靶向和持续递送细胞毒药物，从而有效地抑制肺癌 成长。这项拟议研究的具体目标是：1)纳米工程MSCs用于细胞毒药物的输送 2)检测纳米工程间充质干细胞在小鼠肺原位移植模型中的抗癌效果 癌症。 具体目标1的研究将集中于优化细胞工程策略，以实现高 在不影响其活性或肿瘤归巢特性的情况下，MSCs的细胞毒性有效载荷。紫杉醇将被用作 一种典型的细胞毒性药物。我们将比较简单内吞摄取和(1)TAT多肽的效率 介导胞内递送和(2)纳米颗粒共价偶联到MSC表面用于纳米工程 MSCs。体外研究纳米颗粒对细胞摄取、细胞毒性和分化的影响 与人MSCs共孵育时对人MSCs的潜在杀伤作用及对癌细胞增殖的抑制 将使用纳米工程MSCs来优化输送参数。具体目标2的研究将(I) 利用骨髓间充质干细胞测定紫杉醇在肺肿瘤中的给药动力学和(Ii)优化给药剂量 在小鼠原位肺癌模型中有效地抑制肿瘤生长。 相关性：与肺癌相关的高死亡率需要开发新的 对晚期疾病有效的治疗方法。本申请书中提出的研究将推进 一种新的治疗策略，结合了使用MSCs的主动靶向和使用安全、 无毒媒介。拟议研究的成功完成将提供关键数据，以确定 这一方法的可行性。这些数据对于进一步开发这种基于细胞的独特的临床前研究是至关重要的 目标策略。

Project Summary/Abstract Lack of effective strategies to achieve cytotoxic concentrations of anticancer drugs in deep-seated and metastatic cancers has been a major barrier to improving treatment outcomes in lung cancer. Mesenchymal stem cells (MSCs) possess exquisite tumor homing capabilities, and thus have the potential to selectively deliver anticancer therapies to tumor tissues. A number of previous studies have shown that genetically modified MSCs can be used to deliver anticancer peptides and proteins to tumor tissues. However, MSCs have not been explored so far to deliver small molecules likely because of the difficulty in immobilizing small molecules in cells for sustained duration. The overall objective of this study is to investigate the efficacy of nano-engineered MSCs (Nano-MSC) in lung cancer. We hypothesize that MSCs engineered to carry drug-loaded, polymeric nanoparticles will allow for tumor-targeted and sustained delivery of cytotoxic drugs, resulting in effective inhibition of lung tumor growth. The specific aims of the proposed research are to 1) Nano-engineer MSCs for cytotoxic drug delivery and 2) Determine the anticancer efficacy of nano-engineered MSCs in a mouse orthotopic model of lung cancer. Studies in Specific Aim 1 will focus on optimizing the cell engineering strategies to achieve high cytotoxic payload in MSCs without affecting their viability or tumor homing properties. Paclitaxel will be used as a model cytotoxic drug. We will compare the efficiency of simple endocytic uptake against (1) TAT peptide mediated cytosolic delivery and (2) covalent conjugation of nanoparticles to MSC surface for nano-engineering MSCs. In vitro studies examining the effect of nanoparticles on cell uptake, cytotoxicity and differentiation potential against human MSCs as well as inhibition of proliferation of cancer cells when co-incubated with nano-engineered MSCs will be used to optimize the delivery parameters. Studies in Specific Aim 2 will (i) determine the kinetics of paclitaxel delivery to lung tumors using MSCs and (ii) optimize the dose for achieving effective tumor growth inhibition in a mouse orthotopic model of lung cancer. Relevance: High mortality rate associated with lung cancer warrants the development of novel approaches that are effective against advanced disease. The studies proposed in this application will advance a novel therapeutic strategy combining active targeting using MSCs and sustained drug delivery using a safe, non-toxic vector. The successful completion of the proposed studies will provide critical data establishing the feasibility of this approach. Such data is critical for the further preclinical development of this unique, cell-based targeting strategy.