Enhanced Drug Delivery to Metastatic Brain Tumors

增强转移性脑肿瘤的药物输送

• 批准号: 6906443
• 负责人: Keith L. Black
• 金额: $ 32.7万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6906443
• 关键词: antineoplastics; astrocytoma; athymic mouse; blood brain barrier; brain neoplasms; clinical research; drug delivery systems; drug interactions; drug screening /evaluation; electron microscopy; glioblastoma multiforme; human subject; intracellular transport; laboratory rat; liquid chromatography mass spectrometry; metastasis; minoxidil; monoclonal antibody; neoplasm /cancer blood supply; patient oriented research; potassium channel; stimulant /agonist; tight junctions; tissue /cell culture; vascular endothelium; vascular endothelium permeability

DESCRIPTION (provided by applicant): Brain capillary endothelium and its contiguous cells, pericytes and astrocytes, are the structural and functional components of the blood-brain barrier (BBB). Microvessels supplying brain tumors retain characteristics of the BBB, forming a blood-tumor barrier (BTB). While adequate delivery of drugs occurs to systemic tumors, the BTB limits delivery of antineoplastic agents to metastatic brain tumors. Drugs such as Herceptin, which is effective in treating metastatic tumors outside the brain have a high failure rate within the brain due to inadequate delivery across the BTB. The incidence of metastatic brain tumors is ten-fold higher than primary brain tumors. We have demonstrated that calcium-sensitive potassium (KCa) channel agonists selectively increase drug delivery across the BTB, and have postulated the biochemical mechanisms of this selective BTB permeability increase. We also have preliminary data suggesting that ATP-sensitive potassium (KATP) channel agonists selectively increase BTB permeability independent of KCa channels. These novel observations allow for a pharmacological mechanism for selectively increasing drug delivery across the BTB. This proposal will (a) further understand the mechanisms of KCa, and KATP channel activation in increasing BTB permeability and (b) optimize delivery of effective concentrations of drugs to metastatic breast and lung tumors in rats and humans via potassium channel-based mechanisms. We build on our data showing the ability of KCa channel agonists to selectively increase drug delivery across the BTB in rat glioma models and preliminary evidence suggesting that the BTB permeability increase may relate to over expression of KCa channels on glioma cells and tumor capillary endothelium. In this grant we will investigate 5 specific aims. Aim 1: To determine whether KCa and KATP channels are over expressed in metastatic brain tumor microvessels and tumor cells and whether increased expression correlates with increased permeability induced by KCa and KATP agonists. To test whether tumor cells can induce over expression of KCa or KATP channels on brain endothelial cells. Aim 2: To test by quantitative electron microscopy whether the mechanism of KATP channel agonist-induced BTB permeability increase is due to increased endothelial vesicular transport or opening of tight junctions. To test whether increased vesicle formation is correlated with changes in endothelial and tumor cell membrane potential. Aim 3: To investigate whether KCa and KATP channel agonists increase delivery of therapeutic monoclonal antibodies and chemotherapeutic drugs across the BTB into metastatic human breast and lung cancer in nude rats/mice. Aim 4: In nude rats/mice harboring metastatic breast and lung tumors we will investigate whether increased drug delivery across the BTB using KCa or KATP agonists results in inhibition of tumor growth, and whether survival is increased. Aim 5: The ability of a KATP channel agonist, minoxidil, to increase delivery of an anti-tumor drug to patients with brain tumors will be determined by LC-MS-MS in resected tumor tissues. This grant is responsive to the recent Brain Tumor PRG recommendation in 2001 to support studies to improve delivery of drugs across the BBB, particularly for metastatic brain tumors. Overall, these studies will further delineate the role of KCa and KATP channel activation as a mechanism for selective delivery of anti-cancer agents across the BTB and could potentially result in improved control of disease in patients with metastatic brain tumors.

描述（由申请人提供）：脑毛细血管内皮及其邻近细胞、周细胞和星形胶质细胞是血脑屏障（BBB）的结构和功能成分。为脑肿瘤供血的微血管保留了血脑屏障的特征，形成血肿瘤屏障（BTB）。虽然对全身性肿瘤进行了充分的药物递送，但 BTB 限制了抗肿瘤药物对转移性脑肿瘤的递送。赫赛汀等药物可有效治疗脑外转移性肿瘤，但由于 BTB 输送不足，在脑内的失败率很高。转移性脑肿瘤的发病率比原发性脑肿瘤高十倍。我们已经证明钙敏感性钾 (KCa) 通道激动剂选择性地增加跨 BTB 的药物输送，并假设了这种选择性 BTB 通透性增加的生化机制。我们还有初步数据表明 ATP 敏感钾 (KATP) 通道激动剂可选择性增加 BTB 通透性，与 KCa 通道无关。这些新的观察结果为选择性增加跨 BTB 的药物输送提供了药理学机制。该提案将（a）进一步了解 KCa 和 KATP 通道激活增加 BTB 通透性的机制，以及（b）通过基于钾通道的机制，优化向大鼠和人类转移性乳腺和肺部肿瘤输送有效浓度的药物。我们的数据显示 KCa 通道激动剂能够选择性地增加大鼠神经胶质瘤模型中 BTB 的药物输送，初步证据表明 BTB 通透性增加可能与 KCa 通道在神经胶质瘤细胞和肿瘤毛细血管内皮上的过度表达有关。在这笔赠款中，我们将研究 5 个具体目标。目标 1：确定 KCa 和 KATP 通道在转移性脑肿瘤微血管和肿瘤细胞中是否过度表达，以及表达增加是否与 KCa 和 KATP 激动剂诱导的通透性增加相关。测试肿瘤细胞是否可以诱导脑内皮细胞上KCa或KATP通道的过度表达。目的 2：通过定量电子显微镜测试 KATP 通道激动剂诱导 BTB 通透性增加的机制是否是由于内皮囊泡运输增加或紧密连接打开所致。测试囊泡形成增加是否与内皮和肿瘤细胞膜电位的变化相关。目标 3：研究 KCa 和 KATP 通道激动剂是否会增加治疗性单克隆抗体和化疗药物穿过 BTB 进入裸鼠/小鼠转移性乳腺癌和肺癌的递送。目标 4：在携带转移性乳腺和肺部肿瘤的裸鼠/小鼠中，我们将研究使用 KCa 或 KATP 激动剂增加跨 BTB 的药物递送是否会导致肿瘤生长的抑制，以及存活率是否会增加。目标 5：通过 LC-MS-MS 在切除的肿瘤组织中测定 KATP 通道激动剂米诺地尔增加向脑肿瘤患者输送抗肿瘤药物的能力。这笔拨款是对 2001 年脑肿瘤 PRG 建议的响应，旨在支持改善跨 BBB 药物输送的研究，特别是针对转移性脑肿瘤。总体而言，这些研究将进一步阐明 KCa 和 KATP 通道激活作为跨 BTB 选择性递送抗癌药物的机制的作用，并可能改善转移性脑肿瘤患者的疾病控制。