How do Nanoparticles Target Cancer? An In Vivo Experimental/Mathematical Study

描述（申请人提供）：根据世界卫生组织的统计，今年（2010年），癌症将成为世界上最大的杀手。纳米技术可能是改变游戏规则所需的，以扭转这一趋势，彻底改变癌症的诊断和治疗。特别是可注射的靶向纳米颗粒（NPs）在寻找、成像和摧毁癌症方面具有巨大的潜力。然而，尽管可用的NP种类繁多，但交付可能仍然是实现其临床承诺的最大障碍。 目前选择NP作为上级生物医学递送载体的范例严重地没有考虑不同NP类型靶向肿瘤的能力。这是因为目前对微尺度上系统注入的NP的动态行为的了解很少。我们已经在活体小鼠中对几种NP类型（具有不同的物理特性，如量子点和纳米管）进行了初步的显微镜实验，这些NP类型在我们测试的NP类型中显示出广泛不同的靶向特征。因此，该建议的主要目的是通过实验观察和数学模型，通过对活体受试者中NP行为的基本理解，指导NP的选择，以最终用于临床成像和治疗的静脉内递送。该提案的最终目的是了解不同大小和形状的NP在活体肿瘤中的靶向行为。NP靶向的详细机制见解可以产生用于针对每个应用的这些代理的智能经验设计的系统（即，通过定制的纳米结构实现药物的个性化）。此外，可以预测使用所选NP进行成像或治疗的最佳时间。因此，这可以使医生有能力选择适当的成像/治疗剂和时间点，这将提高疗效并导致早期癌症检测，提高治疗疗效，并降低基于NP的毒性。 为了了解肿瘤中的纳米颗粒行为，该提案描述了活体显微镜如何用于探索肿瘤组织内和周围的主动，被动和非特异性纳米颗粒相互作用，包括靶向肿瘤血管内皮，外渗和靶向肿瘤细胞表面。然而，单独的活体显微镜检查不足以解释活体动物中的纳米颗粒行为。由于大量的时间，精力和金钱是在选择纳米粒子不适合特定的应用程序，迫切需要存在于生物医学纳米技术社区，严格理解观察到的现象，使用先进的定量模型。该提案描述了数学模型的开发，该模型真实地模拟了纳米颗粒与肿瘤血管的结合，预先验证了选择进入临床前模型的纳米颗粒。与活体实验密切相关的数学建模将有力地相互告知和指导。这将产生一个通用的框架，通过该框架可以选择诊断/治疗纳米颗粒的适当尺寸和形状，以在实验室和最终在临床上进行测试。因此，这将更快地导致癌症靶向纳米颗粒的上级临床应用。

DESCRIPTION (provided by applicant): This year (2010), cancer will become the world's biggest killer according to the World Health Organization. Nanotechnology is likely the game-changer needed to reverse this trend by revolutionizing cancer diagnosis and therapy. Injectable, targeted nanoparticles (NPs) in particular have enormous potential to seek, image, and destroy cancer. Yet despite the enormous diversity of NPs available, delivery remains perhaps the biggest obstacle to the realization of their clinical promise. The current paradigm in the selection of NPs as superior biomedical delivery vehicles critically does not account for the ability of different NP types to target tumor. This is because there currently exists very little understanding about the dynamic behavior of systemically injected NPs on the microscale. We have performed preliminary microscopy experiments on several NP types (with varied physical properties, such as quantum dots and nanotubes) in living mice that display broadly different targeting characteristics across the NP types we have tested. A chief objective of this proposal is therefore to guide selection of NPs for eventual use in intravenous delivery for clinical imaging and therapy by developing a fundamental understanding of NP behavior in living subjects via experimental observation and mathematical models. The proposal ultimately aims to understand the targeting behavior of NPs of diverse size and shape in the tumor of living subjects. Detailed mechanistic insight of NP targeting could yield a system for the intelligent empirical design of these agents for each application (i.e., personalization of medicine via customized nanostructures). Moreover, the optimal times for imaging or therapy with the selected NPs could be predicted. This could thus arm physicians with the ability to select the appropriate imaging/therapeutic agent and time-point, which would increase efficacy and lead to earlier cancer detection, increased therapeutic efficacy, and decreased NP-based toxicity. To understand nanoparticle behavior in tumors, this proposal delineates how intravital microscopy will be used to explore active, passive, and non-specific nanoparticle interactions within and around tumor tissue, including targeting to tumor blood vessel endothelium, extravasation, and targeting to tumor cell surfaces. However, intravital microscopy alone will not be sufficient to explain nanoparticle behavior in living animals. Because much time, effort, and money is forfeit on choosing nanoparticles inappropriate for a given application, an urgent need exists in the biomedical nanotechnology community to rigorously understand observed phenomena using advanced quantitative models. This proposal describes the development of mathematical models that realistically simulate nanoparticle binding to tumor blood vessels, pre-validating the nanoparticles chosen to enter pre-clinical models. Mathematical modeling in intimate association with intravital experiments will robustly inform and guide one another. This will result in a generalized framework by which to choose the appropriate size and shape of diagnostic/therapeutic nanoparticles to test in the lab and eventually in the clinic. This will thus much more rapidly lead to superior clinical applications for cancer-targeted nanoparticles.