FEASIBILITY OF NANOPARTICLE-MEDIATED PACLITAXEL DELIVERY

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 紫杉醇是多种癌症的标准有效化疗药物，包括乳腺癌、卵巢癌、小细胞肺癌和非小细胞肺癌。由于紫杉醇(PTX)在水中的溶解度非常有限，该药物的配方需要乳油EL，这会导致严重的副作用，如过敏反应。因此，接受PTX治疗的患者需要在服用前使用组胺阻滞剂和类固醇。我们建议使用一种新型的水溶性纳米粒制剂来实现PTX的更好的药物传递。这种专利配方在临床前研究中已被证明比目前可用的配方更安全和更有效。例如，暴露于PTX纳米颗粒的一些荷瘤小鼠治愈了癌症，而克莫弗配方没有观察到这一点。本研究的目的是通过使用14C-紫杉醇标记PTX纳米粒，然后在裸鼠体内进行吸收、分布、代谢和排泄(ADME)研究，从而将PTX纳米粒的使用推进到0期临床研究。这些微粒将根据既定的方案进行合成，其中包括在最终的自组装步骤中添加14C-紫杉醇。小鼠将被给予足够比活性的PTX纳米颗粒，以允许通过液体闪烁计数(LSC)进行追踪。LSC实验将允许使用基于AMS的14C-紫杉醇检测来计算重复研究所需的比活度。需要AMS作为项目的一部分，以便预测剂量配方并开发用于临床研究的方法(稍后提出)。预计LSC对人类0期研究有足够的敏感性，但这需要通过拟议的动物实验来建立经验。如果成功，可行性研究数据将被提交给FDA进行探索性的IND应用，以确定PTX纳米颗粒在人体内的药代动力学，从而证明后续的第一阶段研究是合理的。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Paclitaxel (Taxol) is a standard and effective chemotherapeutic for many cancer types, including breast cancer, ovarian cancer, small cell lung cancer and non-small cell lung cancer. Since paclitaxel (PTX) has very limited solubility in water, the formulation of this drug requires Cremophor EL which causes significant side effects, such as allergic reactions. Consequently, patients receiving PTX require premedication with histamine blockers and steroids. We proposed to use a novel water-soluble nanoparticle-based formulation to enable better drug delivery of PTX. This proprietary formulation has been demonstrated to be safer and more effective in preclinical studies compared to currently available formulations. For example, some tumor-bearing mice exposed to PTX-nanoparticles were cured of cancer, which was not observed for the Cremophor formulation. The goal of this study is to advance the use of PTX-nanoparticles into Phase 0 clinical studies by using 14C-paclitaxel to label the nanoparticles followed by absorption, distribution, metabolism and excretion (ADME) studies in nude mice with human tumor xenografts. The particles will be synthesized according to established protocols which includes addition of the 14C-paclitaxel in the final self-assemble step. Mice will be dosed with PTX-nanoparticles of sufficient specific activity to allow tracing by liquid scintillation counting (LSC). The LSC experiments will allow calculation of the specific activity needed for the studies to be repeated using AMS-based detection of the 14C-paclitaxel. AMS is needed as part of the project in order to predict dose formulations and develop methods for use in clinical studies (to be proposed later). It is anticipated that LSC has sufficient sensitivity for human phase 0 studies, but this needs to be established empirically with the proposed animal studies. If successful, the feasibility study data will be submitted to FDA for an exploratory IND application in order to determine the pharmacokinetics of PTX-nanoparticles in humans in order to justify subsequent Phase 1 studies.