Large Scale Synthesis and Biodistribution of Expansile Nanoparticles

描述（由申请人提供）：尽管结合手术、放疗和/或化疗的积极多模式治疗，间皮瘤几乎是一种普遍致命的癌症，大多数患者死于局部复发症状。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，需要新的药物递送方法、生物材料和递送药物活性剂的机制。Ionic Pharmaceuticals正在开发一种新型的基于纳米颗粒的药物递送系统，用于将腹腔内给药的化疗直接定位于手术切除术后残留的既定疾病部位，从而增加肿瘤组织药物浓度，随后减少复发并提高患者生存率。最近的数据表明，在已建立的人腹膜内（IP）间皮瘤小鼠模型中，用紫杉醇负载的可膨胀纳米颗粒治疗（Pax-eNPs）显著（p<0.05 ANOVA）与用溶解在Cremophor/乙醇中的紫杉醇的标准临床制剂（Pax-C/E）治疗相比改善了存活率（中位生存期90天vs. 51天;完全临床应答率66% vs. 16%）。与Pax-C/E相比，Pax-eNPs的上级性能归因于：1）eNPs的肿瘤特异性定位;以及，随后，2）与Pax-C/E相比，当作为Pax-eNPs施用时，紫杉醇的肿瘤组织浓度显著更高（250倍）。在该提议中提出了该技术商业化和该药物递送系统在临床中的使用的三个关键步骤：合成放大、生物分布和临床前测试。因此，该提议的具体目标是：目标1：进行eNP单体（~500 g）和紫杉醇负载的eNP（2 L）的大规模合成;并通过建立放行质量标准和分析优化批间重现性。 目标二：确定C14标记的eNPs的生物分布（IP和血浆-时间过程、组织分布、IP注射后在大鼠中的排泄途径和速率）。 目的3：向纳米技术表征实验室（NCL）提交关于负载紫杉醇的eNPs的进一步临床前测试的提案。 在完成这些I期目标后，我们将提交用于Pax-eNPs的GMP合成以及临床前PK、安全性和毒理学研究的II期SBIR。我们已经与NCL讨论了这个项目，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有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.