Large Scale Synthesis and Biodistribution of Expansile Nanoparticles

描述(申请人提供)：尽管间皮瘤结合了手术、放射和/或化疗的积极的多模式治疗，但间皮瘤是一种几乎普遍存在的致命癌症，大多数患者会死于局部复发的症状。到目前为止，这种疾病还没有有效的治疗方法，也没有办法防止局部复发。因此，需要新的药物传递方法、生物材料和传递药理活性物质的机制。离子制药公司正在开发一种新的基于纳米颗粒的药物输送系统，用于将腹膜内化疗直接定位于手术切除手术后残留的已确定的疾病部位，从而提高肿瘤组织的药物浓度，从而减少复发和改善患者的生存。最近的数据表明，在已建立的人腹膜(IP)间皮瘤小鼠模型中，与标准临床配方的克莫弗/乙醇(Pax-C/E)紫杉醇治疗相比，紫杉醇可膨胀纳米粒(Pax-ENPs)治疗显著提高存活率(P&lt；0.05 ANOVA)(中位生存期90天对51天；完全临床反应66%对16%)。与Pax-C/E相比，Pax-ENPs的优异性能归因于：1)ENPs的肿瘤特异性定位；以及2)当作为Pax-ENPs给药时，肿瘤组织中紫杉醇的浓度显著高于Pax-C/E(250倍)。本方案涉及该技术商业化和临床使用的三个关键步骤：合成放大、生物分布和临床前试验。因此，本方案的具体目标是：大规模合成ENP单体(~500g)和紫杉醇载药ENPs(2 L)；并且，通过建立发布规范和分析来优化批次到批次的重复性。目的：测定C14标记的ENPs在大鼠体内的生物分布(ip和血浆时间进程、组织分布、排泄途径和排泄率)。目标3：向纳米技术表征实验室(NCL)提交一份提案，以进一步进行紫杉醇载药ENPs的临床前测试。在完成这些第一阶段的目标后，我们将提交第二阶段SBIR，用于Pax-ENPs的GMP合成和临床前PK、安全性和毒理学研究。我们已经与NCL讨论了这一项目(见信函)，并将与他们合作和协调我们的活动，以确保这种药物输送技术的高效和严格的开发和商业化。

DESCRIPTION (provided by applicant): Despite aggressive multimodality therapy combining surgery, radiation, and/or chemotherapy, mesothelioma is a nearly universally fatal cancer with the majority of patients succumbing to symptoms of local recurrence. To date, there is no effective cure for this disease and there is no way to prevent local recurrence. Consequently, new drug delivery approaches, biomaterials, and mechanisms to deliver pharmacologically active agents are needed. Ionic Pharmaceuticals is developing a novel nanoparticle-based drug delivery system for localizing intraperitoneally administered chemotherapy directly to the site of established disease that remains following surgical resection procedures, resulting in increased tumor-tissue drug concentrations and, subsequently, reduced recurrence and improved patient survival. Recent data demonstrate that, in a murine model of established, human, intraperitoneal (IP) mesothelioma, treatment with paclitaxel-loaded expansile nanoparticles (Pax-eNPs) significantly (p<0.05 ANOVA) improves survival compared to treatment with the standard clinical formulation of paclitaxel solubilized in Cremophor/ethanol (Pax-C/E) (median survival 90 days vs. 51 days; complete clinical responses 66% vs. 16%). The superior performance of Pax-eNPs compared to Pax-C/E is attributed to: 1) tumor specific localization of eNPs; and, subsequently, 2) significantly higher (250- fold) tumor tissue concentrations of paclitaxel when administered as Pax-eNPs as compared to Pax-C/E. Three critical steps towards commercialization of this technology and the use of this drug delivery system in the clinic are addressed in this proposal: synthetic scale-up, biodistribution, and preclinical testing Thus, the specific aims of this proposal are: Aim 1: Perform large-scale synthesis of eNP monomer (~500 g) and paclitaxel-loaded-eNPs (2 L); and, optimize batch-to-batch reproducibility with establishment of release specifications and analytics. Aim 2: Determine the biodistribution of C14-labeled-eNPs (IP and plasma-time course, tissue distribution, routes and rates of excretion following IP injection in rats). Aim 3: Submit a proposal to the Nanotechnology Characterization Laboratory (NCL) for further pre- clinical testing of the paclitaxel-loaded-eNPs. At the completion of these Phase I aims, we will be positioned to submit a Phase II SBIR for GMP synthesis of Pax-eNPs and pre-clinical PK, safety, and toxicology studies. We have discussed this project with the NCL (see letter) and will collaborate and coordinate our activities with them to ensure an efficient and rigorous development and commercialization of this drug delivery technology.