Drug Retention and Tumor Distribution of Polymeric Micelles for Cancer Therapy

摘要/项目摘要 聚合物胶束是一种具有广阔应用前景的药物载体。目前没有美国食品 和药物管理局批准的聚合物胶束制剂，但有些已被批准的 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 主要集中在两个药物部分-未结合的游离药物和与血清蛋白结合的药物。但 纳米颗粒的加入使药代动力学分析复杂化，因为引入了第三种药物组分， 纳米药物封装。包封到聚合物胶束改变药物分配到血清蛋白。 聚合物胶束可以优先积聚到肿瘤组织中，提高肿瘤药物暴露。之甚少 已知聚合物-药物相互作用如何影响聚合物胶束和血清之间的药物分配 proteins.我的初步数据表明，我们已经开发了一种体外测定胶束蛋白 这种分配重现了已知的体内行为，如药物华法林的高蛋白结合。为 F99阶段，我假设药物的体外分配与聚合物-药物有关 我们通过NMR，micro-DSC和分子动力学观察到的相互作用。特别是，我们已经表明， 药物与部分聚合物胶束亲水冠的相互作用导致药物负载的改善，并且可以 导致在聚合物胶束中更强的保留。在目标1.1中，我建议研究这些测量的聚合物- 药物相互作用影响体外试验中的药物分配。这种体外药物分配可能与 在三阴性乳腺癌小鼠模型中的体内肿瘤药物暴露。在目标1.2中，我假设 如在体外测量的，改进的胶束药物保留将改进药物在体内向肿瘤的分布， 通过AUC和Cmax测量。了解聚合物-药物相互作用如何影响分配和肿瘤 暴露将导致减少临床前研究和改善治疗结果。我们将能够选择 应用体外分配结果进行药代动力学建模以预测肿瘤药物 exposure.在目标1.3中，我们将分析非人灵长类动物中的药物组分，以确定药物分配是否是 在更像人类的物种中重现。总的来说，拟议的F99阶段工作将改善我们的 了解聚合物胶束制剂以及药物保留如何影响肿瘤暴露和治疗 功效在K 00阶段，我建议将重点放在癌症的聚合物-核酸和聚合物-蛋白质复合物上 治疗剂和疫苗。利用来自F99阶段的相同原理，聚合物-货物相互作用可以是： 用于通知这些不同货物的靶向药物递送。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 关于癌症治疗

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.