FEASIBILITY OF NANOPARTICLE-MEDIATED PACLITAXEL DELIVERY

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 紫杉醇（Taxol）是一种标准且有效的化疗药物，用于治疗多种癌症，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，因此该药物的制剂需要Cremophor EL，这会导致显著的副作用，如过敏反应。 因此，接受PTX的患者需要使用组胺阻滞剂和类固醇进行术前用药。 我们建议使用一种新的水溶性纳米颗粒为基础的配方，使更好的药物输送的PTX。 与目前可用的制剂相比，该专利制剂在临床前研究中已被证明更安全，更有效。例如，暴露于PTX纳米颗粒的一些荷瘤小鼠的癌症被治愈，而Cremophor制剂没有观察到。 本研究的目的是通过使用14 C-紫杉醇标记纳米颗粒，然后在具有人肿瘤异种移植物的裸鼠中进行吸收、分布、代谢和排泄（ADME）研究，将PTX-纳米颗粒的使用推进到0期临床研究中。将根据已建立的方案合成颗粒，所述方案包括在最终自组装步骤中添加14 C-紫杉醇。 小鼠将被给予具有足够比活性的PTX-纳米颗粒以允许通过液体闪烁计数（LSC）进行追踪。 LSC实验将允许计算使用基于AMS的14 C-紫杉醇检测重复研究所需的比活性。 需要将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对人体0期研究具有足够的灵敏度，但这需要通过拟定的动物研究根据经验确定。 如果成功，可行性研究数据将提交给FDA进行探索性IND申请，以确定PTX纳米颗粒在人体中的药代动力学，从而证明后续I期研究的合理性。

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.