Pressure-Driven Local Drug Delivery System for Treatment of Liver Cancer

用于治疗肝癌的压力驱动局部给药系统

• 批准号: 8653570
• 负责人: Agata A Exner
• 金额: $ 34.59万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8653570
• 关键词: Ablation; Advanced Development; Adverse effects; Amines; Aphorisms; Area; Behavior; Cell Death; Chemotherapy-Oncologic Procedure; Clinical; Data; Diffusion; Dose; Doxorubicin; Drug Delivery Systems; Drug Formulations; Drug Kinetics; Drug resistance; Environment; Ethylene Oxide; Excision; Experimental Models; Family; Gelatin; Glycolic-Lactic Acid Polyester; Goals; Health; Hepatic; Image; Implant; In Situ; Incidence; Injectable; Interdisciplinary Study; Interventional radiology; Lead; Liver; Liver neoplasms; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of liver; Measurement; Measures; Mechanics; Modeling; Monitor; Morphology; Operative Surgical Procedures; Outcome; Patients; Penetration; Performance; Perfusion; Pharmaceutical Preparations; Pharmacodynamics; Phase; Pluronics; Polymers; Primary carcinoma of the liver cells; Procedures; Rattus; Regimen; Research; Residual state; Resistance; Side; Site; Solid; Solid Neoplasm; Spatial Distribution; Sterile coverings; Swelling; System; Systemic Therapy; Techniques; Testing; Therapeutic; Time; Tissues; Toxic effect; Translations; Treatment Efficacy; Treatment outcome; Tumor Tissue; Ultrasonography; Unresectable; Work; base; cancer cell; chemosensitizing agent; chemotherapy; clinical application; clinical practice; clinically relevant; design; driving force; fluorescence imaging; improved; in vivo; innovation; liver transplantation; local drug delivery; member; minimally invasive; multidisciplinary; oncology; patient population; poly(propylene oxide); pressure; public health relevance; subcutaneous; surfactant; treatment strategy; tumor

DESCRIPTION (provided by applicant): Many patients with hepatic malignancies are not candidates for invasive surgical resection due to poor general health or confounding conditions. In these patients local, minimally invasive, image-guided approaches such as tumor ablation offer promising outcomes when combined with effective chemotherapy. Unfortunately most chemotherapeutic regimens are associated with high systemic toxicities and thus are not the ideal strategy when a minimally invasive approach is desired. Local, injectable drug delivery systems offer an alternative to systemic therapy in these cases, since they can be administered under image guidance, and can focus the bulk of released drug directly at the tumor side avoiding systemic side effects. The overarching goal of this project is to develop an effective image-guided local platform drug delivery system for treatment of solid tumors that can be administered, monitored and controlled by utilizing existing interventional radiology techniques. The proposed delivery system will augment drug penetration into tumor tissue using a unique concept of pressure- driven drug diffusion and will lower the effective drug concentration by incorporating a cancer-selective sensitizer into the formulation along with the active agent. The synergistic combination of increased diffusion and decreased effective drug dose should result in a system that is significantly more effective in treatment of tumors. The work will be carried out in four aims. First, the concept of pressure-induced doxorubicin release will be tested and optimized. In parallel, the local co-delivery of the chemosensitizer will be examined. In the third aim, the local site-specific pharmacokinetics and pharmacodynamics of the delivery system will be determined. Finally, in the last aim the therapeutic efficacy of the optimal delivery system wil be assessed in an experimental model of liver cancer, one of the most difficult to treat with systemic chemotherapy or surgical removal. Injectable local drug delivery formulations designed based on the acquired data will be more effective in treatment of solid tumors and could be the driving force behind a shift in minimally invasive management of cancer.

描述（由申请人提供）：由于一般健康状况不佳或混杂条件，许多肝脏恶性肿瘤患者不适合进行侵入性手术切除。在这些患者中，局部、微创、图像引导的方法（例如肿瘤消融）与有效的化疗相结合可提供有希望的结果。不幸的是，大多数化疗方案都具有较高的全身毒性，因此在需要微创方法时并不是理想的策略。在这些情况下，局部注射药物输送系统提供了全身治疗的替代方案，因为它们可以在图像引导下给药，并且可以将大部分释放的药物直接集中在肿瘤一侧，避免全身副作用。该项目的总体目标是开发一种有效的图像引导局部平台药物输送系统，用于治疗实体瘤，可以利用现有的介入放射学技术进行管理、监测和控制。所提出的递送系统将利用压力驱动药物扩散的独特概念增强药物渗透到肿瘤组织中，并通过将癌症选择性敏化剂与活性剂一起纳入制剂中来降低有效药物浓度。增加扩散和减少有效药物剂量的协同组合应产生一种在肿瘤治疗中显着更有效的系统。工作将围绕四个目标开展。首先，将测试和优化压力诱导阿霉素释放的概念。同时，将检查化学增敏剂的局部共同递送。在第三个 目标，将确定递送系统的局部位点特异性药代动力学和药效学。最后，在最后一个目标中，将在肝癌实验模型中评估最佳输送系统的治疗效果，肝癌是全身化疗或手术切除最难治疗的癌症之一。根据所获得的数据设计的注射局部给药制剂将更有效地治疗实体瘤，并可能成为癌症微创治疗转变的驱动力。