Improving delivery of paclitaxel to ovarian cancer via expansile nanoparticles

通过可膨胀纳米颗粒改善紫杉醇对卵巢癌的递送

• 批准号: 9331301
• 负责人: Aaron Henry Colby
• 金额: $ 28.31万
• 依托单位: IONIC PHARMACEUTICALS
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-15 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9331301
• 关键词: Acidity; Address; Adverse effects; Cells; Cellular Metabolic Process; Characteristics; Clinical; Data; Development; Development Plans; Devices; Diffuse; Disease; Dose; Dose-Limiting; Drug Delivery Systems; Drug Exposure; Drug Kinetics; Encapsulated; Endosomes; Evaluation; Excision; Exhibits; Exposure to; Formulation; Grant; Greater sac of peritoneum; Hour; Hydrophobicity; Hypoxia; In Vitro; Individual; Injection of therapeutic agent; Investigation; Legal patent; Ligands; Lysosomes; Malignant neoplasm of ovary; Maximum Tolerated Dose; Mesothelioma; Microscopic; Modeling; Multi-Drug Resistance; Organ; Outcome; Ovarian; Paclitaxel; Patient-Focused Outcomes; Patients; Peritoneal; Peritoneum; Pharmaceutical Preparations; Phase; Procedures; Recurrence; Recurrent disease; Regimen; Research; Route; Safety; Sampling; Site; Small Business Innovation Research Grant; Surface; Survival Rate; Swelling; Technology; Therapeutic; Tissues; Toxic effect; Treatment Efficacy; Tumor Debulking; Tumor Tissue; Widespread Disease; absorption; base; chemotherapeutic agent; chemotherapy; commercialization; comparative efficacy; cytotoxicity; drug clearance; good laboratory practice; improved; innovation; intraperitoneal; intraperitoneal therapy; nanoparticle; neoplastic cell; new technology; novel; novel therapeutics; oncology; ovarian neoplasm; particle; pre-clinical; preclinical development; prevent; prospective; relapse patients; response; success; technology development; toxicity characteristics; tumor; tumor metabolism; tumor microenvironment; tumor specificity; uptake

ABSTRACT A primary challenge in ovarian cancer is preventing tumor recurrence in patients following a resection / debulking procedure (5-year survival rate <45%). Intraperitoneal (IP) administration of chemotherapy (most notably paclitaxel) can improve patient outcomes and prevent local tumor recurrence (the principal deterrent to long-term survival). However, despite these modest improvements, there are significant limitations to this therapy. For example, the current clinical formulation of paclitaxel (i.e., Taxol®) is: A) limited due to toxic side effects resulting from absorption across the entire surface of the peritoneal cavity with no mechanism for tumor specificity; and, B) rapidly cleared from the peritoneal cavity (<10% remaining after 6 hours) resulting in sub- therapeutic levels within the tumor tissue. The proposed research uses a novel, patented technology, the expansile nanoparticle (eNP), to target the primary observable cause of patient relapse (locally recurrent IP tumor) and address these challenges. eNPs decrease toxicity and increased efficacy via: a) unique Materials- Based Targeting, which leads to preferential uptake in tumors; and, b) triggered drug release following particle swelling, which occurs in response to exposure to lowered pH (5-6.5) found in the tumor microenvironment or in the endosomes of tumor cells. Preliminary data demonstrate that, following IP administration, paclitaxel- loaded-eNPs (PTX-eNPs): 1) accumulate in both microscopic (<1 mm) and large (0.5 cm – 1 cm) IP tumors via Materials-based Targeting without the need for targeting ligands—this characteristic is hypothesized to result from: 1a) the rapid metabolism of cancer cells vs. healthy cells; and, 1b) swelling of the eNPs within tumor cells which disrupts endosomal / autophagosomal turnover and leads to intracellular accumulation of eNPs; 2) exhibit greater in vitro cytotoxicity than Taxol against multi-drug resistant patient samples—this is hypothesized to result from the formation of an intracellular “drug depot” upon eNP internalization that overcomes cellular evacuation of drug; 3) deliver 10- to 1000-fold higher intratumoral concentrations of paclitaxel than Taxol over a seven day period following injection; and, 4) reduce the amount of recurrent ovarian tumor by 3-fold (v. Taxol) and more than double survival (v. Taxol) in a multiple-dose treatment of IP mesothelioma model (similarly diffuse/widespread disease presentation in the peritoneum). A key Go/No-Go decision regarding the commercialization of this technology is addressed herein, via: 1) determination of the PTX-eNP maximum tolerated dose (MTD) and identification of target organs and toxicity (which may differ from Taxol due to the pharmacokinetics and distribution of the carrier; i.e., eNPs); and, 2) definitive and robust evaluation of PTX-eNPs v. Taxol to determine the value of further preclinical development of this technology. Thus, the aims are: Aim 1) Determine the MTD of PTX-eNPs, the target organs and characteristic toxicity when administered IP; and, Aim 2) Determine the maximum efficacy of PTX-eNPs in treating ovarian cancer.

摘要