Enhanced Intraarterial Delivery of Chemotherapeutic Drugs to the Brain

增强化疗药物向大脑的动脉内输送

• 批准号: 8307027
• 负责人: SHAILENDRA JOSHI
• 金额: $ 35.42万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8307027
• 关键词: Affect; American; Anesthesia procedures; Antineoplastic Agents; Blood - brain barrier anatomy; Blood Cells; Blood capillaries; Blood flow; Bolus Infusion; Brain; Brain Diseases; Brain Neoplasms; Brain imaging; Brain region; Cerebrovascular Circulation; Cerebrum; Cessation of life; Characteristics; Clinical; Clinical Protocols; Complex; Data; Daunorubicin; Deposition; Development; Diffusion; Distal; Drug Delivery Systems; Drug Kinetics; Effectiveness; Employee Strikes; Face; Frequencies; Glioma; Health Care Costs; Hyperventilation; Hypotension; In Situ; Injection of therapeutic agent; Interruption; Intra-Arterial Injections; Kinetics; Lead; Left; Life; Lipids; Malignant neoplasm of brain; Measurement; Measures; Methods; Mitoxantrone; Modeling; Monitor; Morbidity - disease rate; Neurologic; Operative Surgical Procedures; Optics; Paclitaxel; Partition Coefficient; Patients; Penetration; Perfusion; Pharmaceutical Preparations; Population; Protein Binding; Protocols documentation; Regional Blood Flow; Relative Risks; Research; Rest; Risk; Role; Safety; Site; Speed; Stream; Techniques; Technology; Therapeutic Agents; Therapeutic Effect; Therapeutic Intervention; Time; Tissues; Topotecan; Treatment Protocols; Tumor Tissue; Water; artery occlusion; base; brain tissue; capillary; cerebral artery; cerebral hypoperfusion; cranium; disability; improved; insight; lipid solubility; molecular pathology; mortality; natural hypothermia; new technology; novel; preclinical study; public health relevance; research study; therapeutic gene; therapeutic protein; tumor; uptake; virtual

DESCRIPTION (provided by applicant): Primary and secondary brain tumors are a leading cause of morbidity and mortality in the general American population. In recent years an enormous effort has been made to deliver drugs to the brain by targeting specific molecules or transport mechanisms across the blood brain barrier. Attempts to selectively deliver chemotherapeutic drugs to the brain by direct intra-arterial injection have not found wide clinical acceptance because of inadequate control of tissue drug concentrations, and the lack of a method to rigorously investigate the fast kinetics of intra-arterial drugs in pre-clinical studies. During the last decade considerable advances have been made in endovascular surgery. The development of microcatheters that are capable of manipulating blood flow and selectively delivering drugs to specific regions of the brain, can greatly improve the safety and efficacy of intra-arterial drugs. The application will show that modifying the blood flow and bolus injection characteristics can dramatically enhance intra-arterial delivery of drugs to the brain. We seek to investigate the effects of manipulating cerebral blood flow and bolus configuration on intra-arterial delivery of chemotherapeutic drugs to normal brain and tumor tissues, so as to maximize regional deposition of the drugs. We will further investigate the role of lipid solubility in enhancing drug delivery to the brain, particularly when the regional blood flow is transiently (30- 60s) reduced. Understanding the kinetics of intra-arterial drugs whose concentrations change rapidly after injection, requires high-speed in-situ measurements. Thus, insight into intra-arterial drug kinetics has hitherto been limited to only a few studies. This application uses the recently developed Optical Pharmacokinetics (OP) technique to measure regional drug concentrations in the brain. OP tracks tissue drug concentrations in virtual real time (50 ms/measurement). We will apply the OP measurements for the first time to the brain. OP measurements are made through the inner table of the skull; therefore, the brain tissue integrity is not compromised. In summary, the proposed research will improve methods of drug delivery to the brain. It will enhance the safety and efficacy of intra-arterial chemotherapeutic drugs. It will lead to new protocols for the treatment of brain cancers. Public Health Relevance: The proposed research which uses novel optical technology and new techniques of intraarterial drug delivery, will considerably advance the understanding of intraarterial drug kinetics. It will lead to new protocols for delivery of chemotherapeutic drugs for treating brain cancers.

描述（由申请人提供）：原发性和继发性脑肿瘤是美国普通人群发病和死亡的主要原因。近年来，人们做出了巨大的努力，通过靶向特定分子或跨血脑屏障的转运机制将药物输送到大脑。由于对组织药物浓度控制不充分，并且在临床前研究中缺乏严格研究动脉内药物快速动力学的方法，通过直接动脉内注射选择性地将化疗药物递送至大脑的尝试尚未获得广泛的临床接受。在过去的十年中，血管内手术取得了长足的进步。开发能够操纵血流并选择性地将药物输送到大脑特定区域的微导管，可以大大提高动脉内药物的安全性和有效性。该应用将表明，改变血流和推注特性可以显着增强动脉内药物向大脑的输送。我们试图研究操纵脑血流和推注配置对化疗药物动脉内输送至正常脑和肿瘤组织的影响，从而最大限度地提高药物的区域沉积。我们将进一步研究脂溶性在增强药物向大脑输送方面的作用，特别是当局部血流量暂时（30-60 秒）减少时。了解注射后浓度迅速变化的动脉内药物的动力学，需要高速原位测量。因此，迄今为止，对动脉内药物动力学的了解仅限于少数研究。该应用程序使用最近开发的光学药代动力学（OP）技术来测量大脑中的区域药物浓度。 OP 虚拟实时跟踪组织药物浓度（50 毫秒/测量）。我们将首次将 OP 测量应用于大脑。 OP 测量是通过颅骨内板进行的；因此，脑组织的完整性不会受到损害。总之，拟议的研究将改进向大脑输送药物的方法。它将提高动脉化疗药物的安全性和有效性。它将导致治疗脑癌的新方案。 公共卫生相关性：拟议的研究使用新型光学技术和动脉内药物输送新技术，将大大增进对动脉内药物动力学的理解。它将产生用于治疗脑癌的化疗药物的新方案。

项目成果

Optically measured NADH concentrations are unaffected by propofol induced EEG silence during transient cerebral hypoperfusion in anesthetized rabbits.

在麻醉兔子短暂脑灌注不足期间，光学测量的 NADH 浓度不受异丙酚诱导的 EEG 沉默的影响。

• DOI: 10.1016/j.brainres.2011.04.002
• 发表时间: 2011
• 期刊: Brain research
• 影响因子: 2.9
• 作者: Wang,Mei;Agarwal,Sachin;Mayevsky,Avraham;Joshi,Shailendra
• 通讯作者: Joshi,Shailendra

Paradoxical increase in the bispectral index during deep anesthesia in New Zealand white rabbits.

• 发表时间: 2014
• 期刊: Journal of the American Association for Laboratory Animal Science : JAALAS
• 作者: A. Romanov;Rajinder-Singh Moon;Mei Wang;S. Joshi

Transient cerebral hypoperfusion assisted intraarterial cationic liposome delivery to brain tissue.

• DOI: 10.1007/s11060-014-1421-6
• 发表时间: 2014-05
• 期刊: JOURNAL OF NEURO-ONCOLOGY
• 影响因子: 3.9
• 作者: Joshi, Shailendra;Singh-Moon, Rajinder P.;Wang, Mei;Chaudhuri, Durba B.;Holcomb, Mark;Straubinger, Ninfa L.;Bruce, Jeffrey N.;Bigio, Irving J.;Straubinger, Robert M.
• 通讯作者: Straubinger, Robert M.

Cationic surface charge enhances early regional deposition of liposomes after intracarotid injection.

• DOI: 10.1007/s11060-014-1584-1
• 发表时间: 2014-12
• 期刊: JOURNAL OF NEURO-ONCOLOGY
• 影响因子: 3.9
• 作者: Joshi, Shailendra;Singh-Moon, Rajinder;Wang, Mei;Chaudhuri, Durba B.;Ellis, Jason A.;Bruce, Jeffrey N.;Bigio, Irving J.;Straubinger, Robert M.
• 通讯作者: Straubinger, Robert M.

Revisiting intra-arterial drug delivery for treating brain diseases or is it "déjà-vu, all over again"?

• DOI: 10.4103/2348-0548.130386
• 发表时间: 2014-05
• 期刊: Journal of neuroanaesthesiology and critical care
• 作者: Joshi S;Ellis JA;Emala CW
• 通讯作者: Emala CW