FEASIBILITY OF NANOPARTICLE-MEDIATED PACLITAXEL DELIVERY

纳米粒子介导的紫杉醇递送的可行性

• 批准号: 8171694
• 负责人: KIT S LAM
• 金额: $ 1.7万
• 依托单位: UNIVERSITY OF CALIF-LAWRNC LVRMR NAT LAB
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8171694
• 关键词: ADME Study; Adverse effects; Albumin-Stabilized Nanoparticle Paclitaxel; Allergic Reaction; Animals; Clinical Research; Computer Retrieval of Information on Scientific Projects Database; Cremophor; Data; Detection; Dose; Drug Delivery Systems; Drug Formulations; Drug Kinetics; Feasibility Studies; Funding; Goals; Grant; Histamine; Human; Institution; Label; Liquid substance; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; Methods; Mus; Non-Small-Cell Lung Carcinoma; Nude Mice; Paclitaxel; Patients; Phase; Premedication; Protocols documentation; Research; Research Personnel; Resources; Scintillation Counting; Solubility; Source; Steroids; United States National Institutes of Health; Water; base; cancer type; cremophor EL; lung small cell carcinoma; malignant breast neoplasm; nanoparticle; novel; particle; phase 1 study; preclinical study; research study; tumor; tumor xenograft

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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 紫杉醇（Taxol）是许多癌症类型的标准且有效的化疗药物，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，因此该药物的配方需要 Cremophor EL，这会导致严重的副作用，例如过敏反应。 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型的水溶性纳米颗粒制剂来实现更好的 PTX 药物输送。 与目前可用的配方相比，这种专有配方在临床前研究中已被证明更安全、更有效。例如，一些暴露于 PTX 纳米颗粒的荷瘤小鼠的癌症得到治愈，而 Cremophor 制剂则没有观察到这种情况。 本研究的目标是通过使用 14C-紫杉醇标记纳米颗粒，然后在人类肿瘤异种移植裸鼠中进行吸收、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。这些颗粒将根据既定方案合成，其中包括在最终自组装步骤中添加 14C-紫杉醇。 将给小鼠服用具有足够比活性的 PTX 纳米颗粒，以便通过液体闪烁计数 (LSC) 进行追踪。 LSC 实验将允许计算使用基于 AMS 的 14C-紫杉醇检测重复研究所需的比活性。 该项目需要 AMS 来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 对于人类 0 期研究具有足够的敏感性，但这需要通过拟议的动物研究凭经验确定。 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，从而证明后续一期研究的合理性。