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管理面临未满足的需求。这些患者通常表现为腹膜腔多发性实体瘤和恶性腹水，不能通过全身静脉（iv）治疗进行充分管理。腹膜内（ip）治疗可以将高浓度的药物输送到位于腹腔内的肿瘤，但通常对远处的腹腔外转移无效。这些缺陷可以通过ip和iv联合治疗来克服。事实上，这样的组合已经证明了晚期卵巢癌患者的生存优势。尚未在胰腺癌中测试IP治疗。ip疗法的效用和功效受到两个问题的限制。首先，药物渗透到肿瘤中通常限于肿瘤周边。第二，ip治疗与由于长时间使用留置导管引起的感染和由于局部药物浓度高引起的腹痛有关。本申请的目的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，组织结构和组成是药物在实体瘤中渗透的主要决定因素，并且高肿瘤细胞密度是主要的渗透屏障。我们进一步表明，通过使用诱导细胞凋亡的药物破坏肿瘤结构和降低肿瘤细胞密度，导致药物（在细胞凋亡发生后给药）在实体瘤中更大和更均匀的渗透。这发生在静脉给药或肿瘤周围空间局部给药时。因此，我们假设，通过使用两种制剂的组合可以增强药物递送至位于腹膜腔中的肿瘤，一种制剂快速释放足够的剂量部分以诱导细胞凋亡，另一种制剂缓慢释放剩余剂量以提供持续数月的药物递送，从而消除了留置ip导管的使用并降低了局部毒性。这些制剂可以ip给药，将管理腹膜肿瘤，并且同时将增强iv给药药物的肿瘤递送。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，并开发了紫杉醇负载（聚（丙交酯-共-乙交酯））微球，与市售紫杉醇/Cremophor制剂相比，该微球在携带腹膜人类异种移植肿瘤的小鼠中显示出更大的肿瘤渗透和保留以及上级抗肿瘤活性。该I期申请的两个目的是（a）开发紫杉醇负载的可生物降解的控释聚合物微球，和（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.