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）：脑毛细管内皮及其连续细胞，周细胞和星形胶质细胞是血脑屏障（BBB）的结构和功能成分。供应脑肿瘤的微梗保留了BBB的特征，形成了血肿瘤屏障（BTB）。尽管药物的足够递送到全身性肿瘤中，但BTB限制了抗肿瘤剂传递到转移性脑肿瘤。有效治疗大脑外转移性肿瘤的药物，例如由于整个BTB的递送不足，大脑内的衰竭率很高。转移性脑肿瘤的发生率比原发性脑肿瘤高十倍。我们已经证明，钙敏感的钾（KCA）通道激动剂有选择地增加了整个BTB的药物递送，并假定这种选择性BTB渗透性的生化机制增加。我们还拥有初步数据，表明ATP敏感的钾（KATP）通道激动剂选择性地增加了与KCA通道无关的BTB通透性。这些新颖的观察结果允许有选择性地增加BTB药物递送的药理机制。该提案将（a）进一步了解KCA的机制，以及通过基于钾通道的机制，在大鼠和人类中，在增加BTB渗透性方面的KATP通道激活，以及（b）优化有效浓度的药物向转移性乳腺癌和肺部肿瘤的递送。我们基于我们的数据，表明在大鼠胶质瘤模型中，KCA通道激动剂在BTB中有选择地增加药物递送的能力，并初步证据表明，BTB通透性的增加可能与神经胶质瘤细胞和肿瘤毛细血管内皮的KCA通道的过度表达有关。在这笔赠款中，我们将调查5个具体目标。目标1：确定在转移性脑肿瘤微血管和肿瘤细胞中是否过度表达KCA和KATP通道，以及表达增加是否与KCA和KATP激动剂诱导的渗透性增加相关。测试肿瘤细胞是否可以诱导脑内皮细胞上KCA或KATP通道的表达。 AIM 2：通过定量电子显微镜测试KATP通道激动剂引起的BTB渗透性的增加是由于内皮囊泡转运的增加还是紧密连接的打开。为了测试增加的囊泡形成是否与内皮和肿瘤细胞膜电位的变化相关。 AIM 3：研究KCA和KATP通道激动剂是否会增加BTB的治疗性单克隆抗体和化学治疗药物的递送，以裸体大鼠/小鼠中的转移性人乳腺癌和肺癌。 AIM 4：在具有转移性乳腺癌和肺部肿瘤的裸鼠/小鼠中，我们将研究使用KCA或KATP激动剂在BTB上增加药物的递送是否会导致肿瘤生长的抑制，以及生存率是否增加。 AIM 5：KATP通道激动剂Minoxidil增加向脑肿瘤患者递送抗肿瘤药物的能力，将由LC-MS-MS在切除的肿瘤组织中确定。该赠款对2001年最近的脑肿瘤PRG建议的反应敏感，以支持改善BBB药物递送的研究，特别是对于转移性脑肿瘤。总体而言，这些研究将进一步描述KCA和KATP通道激活作为选择性递送抗癌剂在BTB上的机制的作用，并有可能改善转移性脑肿瘤患者对疾病的控制。