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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的卵巢癌的主要挑战是防止切除后患者的肿瘤复发延期程序（5年生存率<45％）。值得注意的紫杉醇）可以促进患者的结局并防止局部肿瘤复发（主要威慑力量但是，长期生存）。例如在整个腹腔腔体上吸收而没有肿瘤机制产生的影响特异性；肿瘤组织中的治疗水平。扩展纳米颗粒（ENP），以针对患者复发的主要可观察的停止（局部复发IP）肿瘤并应对这些挑战。基于靶向的靶向，导致肿瘤的优先吸收；肿胀是由于暴露于肿瘤微环境中发现的降低的pH（5-6.5）而发生的。在肿瘤细胞的内体中。加载 - ENP（PTX-ENP）：1）通过微观（<1 mm）和大型（0.5 cm-1 cm）IP肿瘤的积累基于材料的靶向靶向配体的需求 - 假设这种特征是结果：1a）癌细胞与健康细胞的快速代谢；肿瘤细胞会破坏内体 /自噬体神经周转率，并导致细胞内积累 ENP; 2）比紫杉醇对多药的样品表现出更大的体外细胞毒性假设是由于ENP内在化的细胞内“药物仓库”形成而导致的克服药物的细胞疏散； 3）注射后的七天，紫杉醇紫杉醇在多剂量治疗中，卵巢肿瘤的3倍（V.紫杉醇）和多剂量生存（V.紫杉醇）间皮瘤模型（腹膜中类似地弥漫/广泛的疾病表现）。关于此处解决此问题的商业化的决定，通过：1）确定 PTX-ENP最大耐受剂量（MTD）和目标器官和毒性的鉴定（可能不同于由于携带者的药代动力学和分布，即ENPS和2） PTX-ENPS V.紫杉醇的评估，以确定该技术进一步临床前开发的价值。因此，目的是：目标1）确定PTX-ENP的MTD，目标器官和特征性毒性管理IP时； 2）确定PTX-ENP在治疗卵巢癌中的最大功效。