Engineered Nanoparticles for Tumor Targeting

虽然早期诊断癌症可以显著提高生存率，但新型纳米技术可以选择性地靶向并摧毁肿瘤细胞，同时不伤害正常细胞，这将减少患者的痛苦和恢复时间。该项目的目标是开发自组装肽-聚合物纳米颗粒，该纳米颗粒可以在治疗计划中以恒定的释放速率靶向高差异剂量的化疗药物到肿瘤支持系统，从而消除有害副作用并提高化疗疗效。假设基于半胱氨酸-缬氨酸（6)-赖氨酸(2)-聚丙交酯-聚富马酸乙二醇酯）大分子的可生物降解自组装肽-聚合物纳米颗粒，由于其尺寸分布狭窄和持续降解的特性，可以在化疗过程中靶向高差异剂量的药物到肿瘤微环境。为了验证这一假设，提出了以下四个任务。在第一个任务中，将结合随机分子动力学和蒙特卡罗方法来模拟多肽-聚合物大分子的化学组成对颗粒结构、大小和降解特性的影响。模拟结果将用于选择聚合粒径为50- 150nm、降解时间为2-6周的肽-聚合物大分子的组成空间中的子空间。在第二项任务中，将实验研究肽-聚合物大分子的化学组成对抗癌药物释放动力学的影响。在第三个任务中，拟肽纳米颗粒将与环精氨酸-甘氨酸-天冬氨酸肽嫁接，该肽与肿瘤细胞上的整合素受体结合具有高特异性，并将确定其对肿瘤细胞结合的影响。在第四项任务中，将在乳腺癌小鼠模型中确定包裹在环肽嫁接纳米颗粒中的抗癌药物的功效。成功与否将由存活率的增加和不良副作用的减少来判断。这项工作的发现有可能将纳米粒子技术从天然或合成聚合物转变为具有工程特性和生物选择性的混合纳米粒子。此外，将获得关于合成的大分子与肽的氨基酸之间的能量相互作用的基本知识，这将最终导致具有新颖工程和生物特性的仿生纳米颗粒的发现。智力上的优点是概念上的证明，具有异常狭窄尺寸分布的拟肽纳米颗粒可以选择性地将高剂量的化疗药物靶向肿瘤微环境，同时不损害正常组织。这项工作更广泛的影响在于将这些想法应用于肿瘤靶向以外的领域，如蛋白质和基因传递、生物标记、病原体检测、生物分子和细胞分离以及成像中的造影剂。制造仿生自组装纳米颗粒的能力，可以选择性地靶向特定的生物分子、细胞器、细胞或组织，不仅在消除化疗副作用方面具有重大突破的潜力，而且还提高了我们对生物材料特性和生物反应之间关系的认识。作为外展计划的一部分，参与该项目的一名博士生将与一名学校教师合作，为中学生设计与纳米技术生物应用相关的实验，并讨论其对教育的潜在影响。

0931998JabbariAlthough diagnosing cancer at an early stage can significantly improve survival rate, novel nanoscale technologies that can selectively target and destroy tumor cells while leaving normal cells unharmed, will reduce patient suffering and recovery time. The goal of this project is to develop self-assembled peptide-polymer nanoparticles that can target a high differential dose of a chemotherapeutic agent at constant release rate during the treatment schedule to the tumor support system, thus eliminating harmful side effects and increasing the efficacy of chemotherapy. It is hypothesized that biodegradable self-assembled peptide-polymer nanoparticles, based on cystine-valine(6)-lysine(2)-poly(lactide-co-glycolide fumarate) macromer, due to their narrow size distribution and constant degradation characteristics, can target a high differential dose of the drug to the tumor microenvironment during the course of chemotherapy. To test this hypothesis, the following four tasks are proposed. In the first task, combination of stochastic molecular dynamic and Monte Carlo methods will be used to simulate the effect of chemical composition of the peptide-polymer macromer on particle structure, size, and degradation characteristics. The simulation results will be used to select a subspace in the composition space of the peptide-polymer macromer with 50-150 nm aggregate size and 2-6 weeks degradation time. In the second task, the effect of chemical composition of the peptide-polymer macromer on release kinetics of the cancer drug will be investigated experimentally. In the third task, peptidomimetic nanoparticles will be grafted with the cyclic arginine-glycine-aspartic acid peptide that binds with high specificity to integrin receptors on tumor cells and its effect on tumor cell binding will be determined. In the fourth task, the efficacy of the cancer drug, encapsulated in cyclic peptide grafted nanoparticles, will be determined in a mouse model of breast cancer. Success will be judge by the increase in survival rate and reduction in undesired side effects. The finding of this work has the potential to transform nanoparticle technology from natural or synthetic polymers to hybrid NPs possessing engineering properties as well as biological selectivity. Furthermore, fundamental knowledge will be gained on energetic interaction between the synthetic macromer and amino acids of the peptide which will ultimately result in the discovery of biomimetic nanoparticles with novel engineering as well as biological properties. The intellectual merit is the proof-of-concept that peptidomimetic nanoparticles with unusually narrow size distribution can selectively target high differential doses of a chemotherapeutic agent to tumor microenvironment, while leaving normal tissues unharmed. The broader impact of this work lies in the application of these ideas to areas other than tumor targeting, like protein and gene delivery, biological labeling, detection of pathogens, separation of biological molecules and cells, and as contrast agent in imaging. The ability to fabricate biomimetic self-assembled nanoparticles that can selectively target specific biomolecules, organelles, cells, or tissues not only has the potential for significant breakthroughs in eliminating side effects of chemotherapy but it also advances our knowledge of the relation between biomaterial property and biological response. As part of the outreach program, a doctoral student involved in this project will work with a school teacher to design experiments related to biological applications of nanotechnology for middle school students and to discuss its potential impact on education.