Image-guided tumor drug delivery by ultrasound-detected heat-released liposome

通过超声检测的热释放脂质体进行图像引导的肿瘤药物递送

• 批准号: 8773087
• 负责人: Ashish Ranjan
• 金额: $ 42.28万
• 依托单位: OKLAHOMA STATE UNIVERSITY STILLWATER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-09 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8773087
• 关键词: Address; Adverse effects; Antineoplastic Agents; Behavior; Blood Vessels; Body Temperature; Buffers; Caliber; Cell membrane; Cells; Chemotherapy-Oncologic Procedure; Clinical; Contrast Media; Dose; Doxorubicin; Doxorubicin Hydrochloride Liposome; Drug Delivery Systems; Drug Exposure; Drug Extravasation; Drug resistance; Drug toxicity; Drug usage; Encapsulated; Environment; Exposure to; Fluorescence Microscopy; Focused Ultrasound Therapy; Goals; Health Sciences; Heating; High Pressure Liquid Chromatography; Hyperthermia; Hypoxia; Image; In Vitro; Induced Hyperthermia; Intercellular Fluid; Investigation; Learning; Libraries; Liposomes; Local Hyperthermia; Magnetic Resonance; Measures; Mediating; Monitor; Normal tissue morphology; Oklahoma; Outcome; Pathway interactions; Perfusion; Permeability; Pharmaceutical Preparations; Physicians; Physiological; Recurrence; Research; Spatial Distribution; Specificity; Speed; Structure; Technology; Temperature; Testing; Time; Tissues; Training; Translational Research; Translations; Treatment Efficacy; Tumor Tissue; Ultrasonography; Universities; antitumor drug; base; cold temperature; cost effectiveness; design; dosage; drug distribution; experience; graduate student; improved; in vivo; innovation; mouse model; nanocarrier; neoplastic cell; novel; perfluoropentane; pressure; prevent; programs; public health relevance; response; success; tumor; tumor specificity; undergraduate student; uptake

DESCRIPTION: Cancer chemotherapy employs systemic delivery of antitumor drugs with limited specificity, causing toxic side effects in normal tissues and inefficient/insufficient drug delivery to tumor cells, leading to recurrence. To address these problems, liposomal stealth drug delivery systems (e.g. Doxil) have been developed to selectively accumulate in tumors, permitting enhanced intratumoral drug delivery while reducing drug exposure and toxicity to normal tissue. However, available clinically-approved nanocarriers release their payload only within the perivascular space of tumors, impeding or preventing distribution to poorly-perfused remote cells in the tumor core that contribute to drug resistance and tumor recurrence. Thus the tumor-directed dose escalations achieved to date via stealth liposome technology have not yet improved treatment efficacy. To overcome these limitations, the long-term goal of our research is to optimize and provide uniform intratumoral delivery of antitumor drugs with real-time control, thereby providing physicians more precise dosing control. In preliminary studies we achieved improved intratumoral distribution of systemically administered doxorubicin (Dox), within tumor periphery and core alike, by inducing rapid intravascular Dox release from Low Temperature-Sensitive Liposomes (LTSL), a technology that permits induction of liposomal drug release using mild local elevations in tissue temperature. The objective of the proposed project is to test the feasibility of and validate an innovative approach for homogeneous, tightly-controlled intratumor delivery of antineoplastic drugs using novel ultrasound-imageable echogenic LTSL (E-LTSL), that will permit image-guided drug delivery (IGDD)-based therapy. We hypothesize that E-LTSL will permit real-time control and monitoring of the release of liposome-encapsulated drugs. By combination with local hyperthermia applied precisely using High-intensity Focused Ultrasound (HIFU), this will allow thermally-induced liposomal drug release, providing enhanced intratumoral drug delivery to otherwise inaccessible tumor cells. The concept builds upon our expertise in biodegradable LTSL synthesis and their application in magnetic resonance-high intensity focused ultrasound- based IGDD. The Specific Aims are: 1: To optimize in vitro and in vivo stability, release and imageability of E- LTSL. 2: To determine E-LTSL-mediated doxorubicin delivery, distribution and efficacy in vivo, using a mouse model. This cutting-edge translational research will enhance the research environment and capabilities of our Center for Veterinary Health Sciences at Oklahoma State University, will provide a rich training and learning experience for our graduate and undergraduate students, and will provide an innovative pathway to improve cancer chemotherapy outcomes by strategically modifying currently approved therapies.

描述：癌症化学疗法采用特异性有限的抗肿瘤药物的全身递送，导致正常组织中的毒性副作用和药物效率低下 传递到肿瘤细胞，导致复发。为了解决这些问题，已经开发出脂质体隐形药物递送系统（例如Doxil）以选择性地积累肿瘤，从而可以增强肿瘤内药物的递送，同时减少对正常组织的药物暴露和毒性。然而，可用的临床批准的纳米载体仅在肿瘤周血管周围释放其有效载荷，阻碍或阻止在肿瘤核中分布到肿瘤核心较差的偏远细胞，从而有助于耐药性和肿瘤复发。因此，迄今为止通过隐形脂质体技术实现的肿瘤定向剂量升级尚未提高治疗功效。为了克服这些局限 从而为医生提供更精确的剂量控制。在初步研究中，我们通过诱导使用脂质体释放的技术释放脂肪体释放的技术，利用脂质体释放的技术释放了脂质体释放的技术，从而改善了肿瘤周围和核心中系统施用的肿瘤内分布，在肿瘤周围和核心中的肿瘤内分布。拟议项目的目的是测试 使用新型的超声可刺激的回声LTSL（E-LTSL），可以允许图像引导的药物输送（IGDD）基于基于图像引导的药物（IGDD） - 基于基于图像引导的治疗方法，并验证了一种均质，紧密控制的抗肿瘤药物的均匀，紧密控制的肿瘤内药物的可行性和验证方法。我们假设E-LTSL将允许实时控制脂质体封装药物的释放。通过与局部高温使用高强度聚焦超声（HIFU）相结合，这将允许热诱导的脂质体药物释放，从而提供了增强的肿瘤内药物递送，从而使其他无法接近的肿瘤细胞。该概念基于我们在可生物降解的LTSL合成中的专业知识及其在基于磁共振高强度的基于超声的IGDD中的应用。具体目的是：1：优化E-LTSL的体外和体内稳定性，释放和可成像性。 2：使用小鼠模型确定E-LTSL介导的阿霉素的递送，分布和疗效。这项尖端的翻译研究将增强俄克拉荷马州立大学兽医健康科学中心的研究环境和能力，将为我们的研究生和本科生提供丰富的培训和学习经验，并将通过战略性地修改当前认可的治疗疗法，为改善癌症化学疗法的成果提供创新的途径。