Improving delivery of paclitaxel to ovarian cancer via expansile nanoparticles

摘要 卵巢癌的主要挑战是预防切除术后患者的肿瘤复发。 减瘤术（5年生存率<45%）。腹膜内（IP）化疗（大多数 尤其是紫杉醇）可以改善患者的预后并防止局部肿瘤复发（主要阻止 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限制 疗法例如，紫杉醇的当前临床制剂（即，Taxol®）：A）由于毒性副作用而受到限制 腹膜腔整个表面吸收产生的效应，无肿瘤机制 特异性;和，B）从腹膜腔快速清除（6小时后剩余<10%），导致亚- 肿瘤组织内的治疗水平。这项拟议中的研究使用了一种新颖的专利技术， 可膨胀纳米颗粒（eNP），以靶向患者复发的主要可观察原因（局部复发性IP #21453;，并应对这些挑战。eNPs通过以下方式降低毒性并提高功效： 基于靶向，其导致肿瘤中的优先摄取;和，B）在颗粒形成后触发药物释放。 肿胀，其响应于暴露于肿瘤微环境中发现的降低的pH（5-6.5）而发生，或 在肿瘤细胞的核内体中。初步数据表明，IP给药后，紫杉醇- 负载的eNPs（PTX-eNPs）：1）通过以下途径在显微镜下（<1 mm）和大（0.5cm-1cm）IP肿瘤中积累： 基于材料的靶向，而不需要靶向配体-这一特征被假设为 这是由于：1a）癌细胞相对于健康细胞的快速代谢;以及，1b）在细胞内的eNPs的膨胀。 肿瘤细胞，其破坏内体/自噬体周转，并导致细胞内积聚 eNPs; 2）对多药耐药患者样品表现出比紫杉醇更大的体外细胞毒性-这 假设是由eNP内化后细胞内“药物贮库”的形成引起的， 克服了药物的细胞排泄; 3）递送10至1000倍更高的肿瘤内浓度的 注射后7天内，紫杉醇比紫杉醇更有效;以及，4）减少复发的数量 IP多次给药治疗中卵巢肿瘤的生存率提高3倍（v. Taxol）和2倍以上（v. Taxol） 间皮瘤模型（腹膜中类似的弥漫/广泛疾病表现）。A键通/止 关于该技术的商业化的决定在本文中通过以下方式来解决：1）确定 PTX-eNP最大耐受剂量（MTD）和靶器官和毒性的鉴定（其可能不同于PTX-eNP）。 由于载体的药代动力学和分布，eNPs）;以及，2）确定性和稳健性 评估PTX-eNPs与紫杉醇的对比，以确定该技术的进一步临床前开发的价值。 因此，目的是：目的1）确定PTX-eNPs的MTD、靶器官和特征毒性 目的2）确定PTX-eNPs在治疗卵巢癌中的最大功效。

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.