Apoptosis Inducing to Enhance Tumor Targeting

诱导细胞凋亡以增强肿瘤靶向

基本信息

批准号：
6799339
负责人：
ZE LU
金额：
$ 24.92万
依托单位：
OPTIMUM THERAPEUTICS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-09-16 至 2006-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6799339
关键词：
apoptosis biodegradable product chemical synthesis clearance rate drug delivery systems drug design /synthesis /production intraperitoneal injections intravenous administration laboratory mouse microcapsule neoplasm /cancer chemotherapy neoplasm /cancer pharmacology neoplastic process paclitaxel peritoneum neoplasm slow release drug

项目摘要

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.

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。这些患者通常在腹膜腔中出现多种实体瘤和恶性腹水，而这些患者没有通过全身性静脉内（IV）治疗来充分控制。腹膜内（IP）疗法可以为位于腹膜腔中的肿瘤提供高药物浓度，但通常对远处的腹外转移无效。这些缺陷可以通过结合IP和IV处理来克服。实际上，这种组合在晚期卵巢癌患者中表现出了生存优势。 IP治疗尚未在胰腺癌中进行测试。 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仅限于肿瘤周围。其次，由于局部药物浓度较高，IP疗法与长期使用留置导管和腹痛有关，与感染有关。该应用的目的是开发可以克服这两个问题的药物输送配方。我们已经证明，组织结构和组成是实体瘤药物渗透的主要决定因素，而高肿瘤细胞密度是主要的穿透性屏障。我们进一步表明，通过使用诱导凋亡的药物，肿瘤结构的破坏和肿瘤细胞密度的降低导致在实体瘤中导致药物越来越均匀的渗透（在凋亡发生后施用）。这是针对静脉注射药物或在周围空间区域内发生的。 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.可以给出这些配方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，并且已经形成了紫杉醇载荷（聚（乳酸 - 糖）微球的紫杉醇，表现出更大的肿瘤渗透和保留率更大，并且在亲属腹膜型群中，与围绕腹膜的抗蛋白酶相比，它们具有更大的抗肿瘤，以及抗肿瘤的抗肿瘤活性。该阶段应用的两个目的是（a）发展紫杉醇负载，可生物降解的可控释放释放聚合物微球，以及（b）确定IP紫杉醇微球的肿瘤靶向优势和抗肿瘤活性。