Engineered Nanoparticles for Tumor Targeting

虽然早期诊断癌症可以显著提高存活率，但新的纳米级技术可以选择性地靶向并摧毁肿瘤细胞，而不损害正常细胞，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的多肽-聚合物纳米颗粒，该纳米颗粒可以在肿瘤支持系统的治疗计划中以恒定的释放速率靶向高不同剂量的化疗药物，从而消除有害副作用并提高化疗的疗效。基于富马酸(cystine-valine(6)-lysine(2)-poly(lactide-co-glycolide)大分子聚合物的可生物降解自组装肽-聚合物纳米粒，由于其窄的尺寸分布和恒定的降解特性，可以在化疗过程中靶向肿瘤微环境的高差别剂量药物。为了验证这一假设，提出了以下四项任务。在第一个任务中，将使用随机分子动力学和蒙特卡罗方法相结合的方法来模拟多肽-聚合物大分子的化学组成对粒子结构、尺寸和降解特性的影响。模拟结果将用于在聚集体尺寸为50-150 nm、降解时间为2-6周的多肽-聚合物大分子的组成空间中选择一个子空间。在第二个任务中，将通过实验研究多肽-聚合物大分子单体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，拟肽纳米粒将与与肿瘤细胞上的整合素受体高度特异性结合的环状精氨酸-甘氨酸-天冬氨酸多肽进行嫁接，并将其对肿瘤细胞结合的影响进行测定。在第四项任务中，这种被包裹在环肽嫁接纳米颗粒中的抗癌药物的疗效将在乳腺癌的小鼠模型中进行测定。成功与否将由存活率的提高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颗粒技术从天然或合成聚合物转变为具有工程性质和生物选择性的杂化纳米颗粒。此外，还将获得合成的大分子单体与多肽的氨基酸之间的能量相互作用的基础知识，最终将发现具有新的工程和生物学特性的仿生纳米颗粒。理论上的优点是概念证明，具有异常狭窄的尺寸分布的模拟肽纳米颗粒可以选择性地将高不同剂量的化疗药物靶向肿瘤微环境，同时使正常组织不受损害。这项工作的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、生物分子和细胞的分离以及作为成像中的造影剂。制备能够选择性靶向特定生物分子、细胞器、细胞或组织的仿生自组装纳米颗粒的能力不仅有可能在消除化疗副作用方面取得重大突破，而且还可以促进我们对生物材料特性和生物反应之间关系的了解。作为推广计划的一部分，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.