Improving delivery of paclitaxel to ovarian cancer via expansile nanoparticles

摘要 卵巢癌的一个主要挑战是防止肿瘤切除后复发。 去髓核手术(5年存活率45%)。腹膜腔内(IP)化疗(MOST 尤其是紫杉醇)可以改善患者的预后并防止局部肿瘤复发(主要威慑 长期生存)。然而，尽管有这些适度的改进，但这方面仍有很大的局限性 心理治疗。例如，目前紫杉醇(即紫杉醇®)的临床配方是：a)由于毒副作用而受到限制 在没有肿瘤发生机制的情况下，通过整个腹膜表面吸收所产生的影响 特异性；以及，B)迅速从腹膜腔清除(6小时后残留10%)，导致亚 肿瘤组织内的治疗水平。这项拟议的研究使用了一项新的专利技术， 可膨胀纳米颗粒(ENP)，针对患者复发的主要可观察原因(局部复发IP 肿瘤)，并应对这些挑战。ENPs通过以下方式降低毒性并提高疗效：a)独特材料- 基于靶向，这导致在肿瘤中优先摄取；以及，b)在颗粒之后触发药物释放 肿胀，由于暴露在较低的PH值(5-6.5)中而发生，在肿瘤微环境或 在肿瘤细胞的内吞体内。初步数据表明，在IP给药后，紫杉醇- 负载型ENPs(PTX-ENPs)：1)在微小(1 Mm)和大(0.5 cm-1 cm)IP肿瘤中通过 基于材料的靶向而不需要靶向配体-假设这一特征是 结果是：1a)癌细胞与健康细胞的快速新陈代谢；以及，1b)内ENPs的肿胀 破坏内吞体/自噬小体周转并导致细胞内蓄积的肿瘤细胞 ENPs；2)对多药耐药患者样本的体外细胞毒性比紫杉醇更大 假设是由于在ENP内化时形成了一个细胞内的“药库” 克服细胞对药物的排出；3)将肿瘤内的浓度提高10到1000倍 在注射后7天内紫杉醇优于紫杉醇；以及，4)减少复发量 多剂量ip治疗卵巢肿瘤3倍(v.Taxol)和双倍以上存活(v.Taxol) 间皮瘤模型(腹膜类似弥漫性/弥漫性疾病表现)。A键去/不去 关于这项技术商业化的决定在这里通过：1)确定 PTX-ENP最大耐受量(MTD)以及靶器官和毒性的识别(可能不同于 紫杉醇，由于载体的药代动力学和分布；以及，2)明确和可靠 评估PTX-ENPs与紫杉醇的对比，以确定该技术进一步临床前开发的价值。 目的：1)确定PTX-ENPs的MTD、靶器官和特征毒性 目的2)确定PTX-ENPs治疗卵巢癌的最大疗效。

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.