Drug Retention and Tumor Distribution of Polymeric Micelles for Cancer Therapy

摘要/项目摘要 聚合物胶束是一种功能强大的药物载体，具有广阔的应用前景。目前没有美国食品 药品监督管理局批准了聚合物胶束配方，但其中一些已经得到了美国食品和药物管理局的批准 欧洲药品管理局和其他国际监管机构。传统药代动力学分析 重点介绍了两种药物成分--游离药物和结合血清蛋白的药物。然而， 通过引入第三个药物组分，纳米颗粒的包含使药代动力学分析变得复杂 纳米药物被封装起来。聚合物胶束的包裹改变了药物对血清蛋白的分配。 聚合物胶束可以优先积聚到肿瘤组织中，改善肿瘤药物的暴露。小才是 了解聚合物-药物相互作用如何影响药物在聚合物胶束和血清之间的分配 蛋白质。我的初步数据显示，我们已经开发出一种体外测试胶束蛋白的方法。 这种分割概括了已知的体内行为，如药物华法林的高蛋白结合。对于 F99阶段我的建议，我假设药物的体外分配与聚合物药物有关 我们通过核磁共振、微观DSC和分子动力学观察到的相互作用。特别是，我们已经证明了 药物与部分聚合物胶束亲水电晕的相互作用导致了药物载量的改善，并且可以 导致在聚合物胶束中有更强的保留力。在目标1.1中，我建议研究这些测量到的聚合物是如何- 在一项有效的体外试验中，药物相互作用影响药物分配。这种体外药物分配可能与 在三阴性乳腺癌小鼠模型中暴露于体内的肿瘤药物。在Aim 1.2中，我假设 改进的胶束药物保留，如在体外测量，将改善药物在体内的分布，如 由AUC和Cmax测量。了解聚合物-药物相互作用如何影响分割和肿瘤 暴露将导致临床前研究减少并改善治疗结果。我们将能够选择 将体外分配结果应用于药物动力学模型预测肿瘤药物的最佳处方 曝光。在目标1.3中，我们将分析非人类灵长类动物中的药物组分，以确定药物分配是否 概括起来就是更像人类的物种。总之，拟议的F99阶段工作将改善我们的 了解聚合物胶束配方以及药物滞留如何影响肿瘤暴露和治疗 功效。在K00阶段，我建议将重点放在癌症的聚合物-核酸和聚合物-蛋白质复合体上 治疗学和疫苗。利用F99相的相同原理，聚合物-货物相互作用可以 用于通知这些不同货物的定向药物递送。我的论文项目和未来的博士后 工作将提供必要的培训经验，为我的独立研究生涯做好准备 癌症治疗方面的研究。

Abstract/Project Summary Polymeric micelles are powerful drug delivery vehicles with a promising future. There are currently no US Food and Drug Administration approved polymeric micelle formulations, but some have been approved by the European Medicines Agency and other international regulatory bodies. Traditional pharmacokinetic analysis focuses on two drug fractions-unbound free drug and drug which is bound to serum proteins. However, the inclusion of nanoparticles complicates pharmacokinetic analysis by introducing a third drug fraction which is nanomedicine encapsulated. Encapsulation into polymeric micelles alters drug partitioning to serum proteins. Polymeric micelles can preferentially accumulate into tumor tissues, improving tumor drug exposure. Little is known about how polymer-drug interactions influence drug partitioning between polymeric micelles and serum proteins. My preliminary data shows that we have developed an in vitro assay to measure micelle-protein partitioning which recapitulates known in vivo behavior, like the high protein binding of the drug warfarin. For the F99 phase of my proposal, I hypothesize that the in vitro partitioning of drug is related to polymer-drug interactions which we observe by NMR, micro-DSC, and molecular dynamics. In particular, we have shown that drug interaction with parts of the polymeric micelle hydrophilic corona leads to improved drug loading, and may lead to stronger retention in the polymeric micelles. In Aim 1.1, I propose to study how these measured polymer- drug interactions affect drug partitioning in a validated in vitro assay. This in vitro drug partitioning could correlate to tumor-drug exposure in vivo in a mouse model of triple negative breast cancer. In Aim 1.2, I hypothesize that improved micelle drug retention, as measured in vitro, will improve the distribution of drug to the tumor in vivo as measured by AUC and Cmax. Understanding how polymer-drug interactions influence partitioning and tumor exposure will lead to reduced preclinical studies and improved therapeutic outcomes. We will be able to select optimal formulations by applying in vitro partitioning results to pharmacokinetic modeling to predict tumor drug exposure. In Aim 1.3, we will analyze drug fractions in non-human primates to determine if drug partitioning is recapitulated in more human-like species. Altogether, the proposed F99 phase work will improve our understanding of polymeric micelle formulations and how drug retention affects tumor exposure and therapeutic efficacy. In the K00 phase, I propose to focus on polymer-nucleic acid and polymer-protein complexes for cancer therapeutics and vaccines. Utilizing the same principles from the F99 phase, polymer-cargo interactions can be used to inform targeted drug delivery of these different cargoes. My dissertation project and future postdoctoral work will provide the necessary training experience to prepare me for an independent research career focused on cancer therapeutics.