Apoptosis Inducing to Enhance Tumor Targeting

描述(由申请人提供)： 转移性胰腺癌和卵巢癌患者的治疗面临着未得到满足的需求。这些患者通常表现为腹膜腔内的多发性实体瘤和恶性腹水，不能通过系统静脉(IV)治疗进行充分的治疗。腹膜内(IP)治疗可以将高浓度的药物输送到位于腹膜腔内的肿瘤，但通常对腹外远处转移无效。这些缺陷可以通过联合ip和iv治疗来克服。事实上，这种联合疗法在晚期卵巢癌患者中显示出了生存优势。IP疗法尚未在胰腺癌中进行测试。IP疗法的实用性和有效性受到两个问题的限制。首先，药物对肿瘤的渗透通常局限于肿瘤的外围。其次，IP治疗与因长时间使用留置导管而引起的感染和因局部药物浓度高而引起的腹痛有关。这项应用的目标是开发能够克服这两个问题的药物递送制剂。 我们已经证明，组织结构和成分是药物在实体肿瘤中渗透的主要决定因素，而高肿瘤细胞密度是主要的渗透障碍。我们进一步表明，通过使用诱导细胞凋亡的药物，肿瘤结构的破坏和肿瘤细胞密度的降低，导致药物在实体肿瘤中的渗透更大和更均匀(在细胞凋亡发生后给药)。这发生在静脉给药，或在瘤周间隙局部给药时。因此，我们假设，通过使用两种制剂的组合，可以增强对位于腹膜腔内的肿瘤的药物输送，一种迅速释放足够部分的剂量以诱导细胞凋亡，另一种缓慢释放剩余剂量以提供持续数月的药物输送，从而消除留置IP导管的使用并降低局部毒性。这些制剂可以给予ip，将管理腹膜肿瘤，同时，将增强静脉注射药物的肿瘤递送。在我们的初步研究中，我们发现紫杉醇对卵巢和胰腺肿瘤细胞具有活性，并且已经开发出紫杉醇(聚丙交酯-乙交酯)微球，与商用紫杉醇/克莫弗制剂相比，该微球在荷人腹膜异种移植瘤的小鼠中表现出更强的肿瘤穿透性和保留性，并具有更好的抗肿瘤活性。这一阶段应用的两个目标是(A)开发紫杉醇载药、可生物降解的控释聚合物微球，以及(B)确定IP紫杉醇微球的肿瘤靶向优势和抗肿瘤活性。

DESCRIPTION (provided by applicant): Management of patients with metastatic pancreatic and ovarian cancer faces unmet needs. These patients usually present with multiple solid tumors and malignant ascites in the peritoneal cavity that are not adequately managed by systemic intravenous (iv) therapy. Intraperitoneal (ip) therapy can deliver high drug concentrations to tumors located in the peritoneal cavity, but is generally not effective against distant extra-abdominal metastases. These deficiencies can be overcome by combining ip and iv treatments. In fact, such combinations have demonstrated a survival advantage in advanced ovarian cancer patients. IP treatment has not been tested in pancreatic cancer. The utility and efficacy of ip therapy are limited by two problems. First, drug penetration into a tumor is usually restricted to the tumor periphery. Second, ip therapy is associated with infection due to prolonged use of indwelling catheters and abdominal pain due to the high local drug concentrations. The objective of this application is to develop drug delivery formulations that can overcome these two problems. We have demonstrated that tissue structure and composition are the major determinants of drug penetration in solid tumors, and that high tumor cell density is a major penetration barrier. We further showed that disruption of tumor structure and reduction of tumor cell density, by using drugs that induce apoptosis, resulted in greater and more even penetration of drug (administered after apoptosis has occurred) in solid tumors. This occurs for drug administered iv, or regionally in the peritumoral space. Hence, we hypothesize that drug delivery to tumors located in the peritoneal cavity can be enhanced by using a combination of two formulations, one that rapidly releases a sufficient fraction of the dose to induce apoptosis and one that slowly releases the remaining dose to provide sustained drug delivery over several months and thereby eliminates the use of indwelling ip catheters and reduces the local toxicity. These formulations can be given ip, will manage the peritoneal tumors, and, at the same time, will enhance the tumor delivery of the iv administered drug. In our preliminary studies, we found that paclitaxel was active against ovarian and pancreatic tumor cells, and have developed paclitaxel-loaded (poly(lactide-co-glycolide)) microspheres that showed greater tumor penetration and retention, and superior antitumor activity in mice bearing peritoneal human xenograft tumors, as compared to the commercial paclitaxel/Cremophor formulation. The two aims of this phase I application are to (a) develop paclitaxel-loaded, biodegradable controlled-release polymeric microspheres, and (b) determine the tumor targeting advantage and antitumor activity of ip paclitaxel microspheres.