Large Scale Synthesis and Biodistribution of Expansile Nanoparticles

可膨胀纳米颗粒的大规模合成和生物分布

• 批准号: 8779193
• 负责人: Aaron Henry Colby
• 金额: $ 22.47万
• 依托单位: IONIC PHARMACEUTICALS
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8779193
• 关键词: Address; Analysis of Variance; Antineoplastic Agents; Asbestos; Biocompatible Materials; Biodistribution; Clinic; Clinical; Combined Modality Therapy; Cremophor; Data; Development; Devices; Diagnosis; Diffuse; Disease; Disease Outcome; Drug Delivery Systems; Drug Formulations; Drug or chemical Tissue Distribution; Encapsulated; Ensure; Ethanol; Excision; Excretory function; Exposure to; Goals; Greater sac of peritoneum; Human; Intraperitoneal Injections; Label; Laboratories; Letters; Malignant - descriptor; Malignant Neoplasms; Mesothelioma; Methods; Modeling; Mus; Nanotechnology; Operative Surgical Procedures; Outcome; Paclitaxel; Patients; Performance; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Plasma; Pleural cavity; Positioning Attribute; Preclinical Testing; Prevention; Procedures; Quality of life; Radiosurgery; Rattus; Recurrence; Regimen; Regulation; Reproducibility; Residual state; Route; Safety; Site; Small Business Innovation Research Grant; Solutions; Survival Rate; Swelling; Symptoms; Technology; Therapeutic; Time; Tissues; Toxicology; Tumor Tissue; Validation; base; chemotherapeutic agent; chemotherapy; commercialization; effective therapy; improved; intraperitoneal; killings; monomer; multimodality; nanoparticle; neoplastic cell; novel; novel strategies; outcome forecast; particle; patient population; phase 1 study; pre-clinical; preclinical study; prevent; public health relevance; research clinical testing; response; scale up; tumor

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.

描述（由申请人提供）：尽管采用了结合手术、放疗和/或化疗的积极多模式治疗，但间皮瘤是一种几乎普遍致命的癌症，大多数患者死于局部复发症状。迄今为止，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、生物材料和递送药理活性剂的机制。 Ionic Pharmaceuticals 正在开发一种新型的基于纳米颗粒的药物输送系统，用于将腹腔内化疗直接定位到手术切除后残留的已确定疾病部位，从而增加肿瘤组织药物浓度，从而减少复发并提高患者生存率。最近的数据表明，在已建立的人类腹膜内 (IP) 间皮瘤小鼠模型中，与标准临床制剂治疗相比，使用负载紫杉醇的可膨胀纳米粒子 (Pax-eNPs) 治疗可显着 (p<0.05 ANOVA) 提高生存率溶解在 Cremophor/乙醇中的紫杉醇 (Pax-C/E)（中位生存期 90 天与 51 天；完全临床反应66% 与 16%）。与 Pax-C/E 相比，Pax-eNPs 的优越性能归因于：1）eNPs 的肿瘤特异性定位；随后，2) 当以 Pax-eNP 形式给药时，与 Pax-C/E 相比，紫杉醇的肿瘤组织浓度显着更高（250 倍）。该提案解决了该技术商业化以及该药物输送系统在临床中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，该提案的具体目标是： 目标 1：进行大规模-eNP单体（约500克）和负载紫杉醇的eNP（2升）的规模合成；并且，通过建立发布规范和分析来优化批次间的再现性。 目标 2：确定 C14 标记的 eNP 的生物分布（IP 和血浆时间进程、组织分布、大鼠 IP 注射后的排泄途径和速率）。 目标 3：向纳米技术表征实验室 (NCL) 提交提案，以对负载紫杉醇的 eNP 进行进一步的临床前测试。 完成这些第一阶段目标后，我们将提交第二阶段 SBIR，用于 Pax-eNP 的 GMP 合成以及临床前 PK、安全性和毒理学研究。我们已经与 NCL 讨论了该项目（见信件），并将与他们合作和协调我们的活动，以确保该药物输送技术的高效、严格的开发和商业化。