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

产品说明：癌症化疗采用特异性有限的抗肿瘤药物全身给药，在正常组织中引起毒副作用，并且药物无效/不足。 递送至肿瘤细胞，导致复发。为了解决这些问题，已经开发了脂质体隐形药物递送系统（例如Doxil）以选择性地在肿瘤中积聚，从而允许增强的肿瘤内药物递送，同时减少药物暴露和对正常组织的毒性。然而，可用的临床批准的纳米载体仅在肿瘤的血管周围空间内释放其有效载荷，阻碍或防止分布到肿瘤核心中的灌注不良的远端细胞，这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递增尚未改善治疗功效。为了克服这些局限性，我们研究的长期目标是优化并提供实时控制的抗肿瘤药物的均匀瘤内递送， 从而为医生提供更精确的剂量控制。在初步研究中，我们通过诱导低温敏感脂质体（LTSL）快速血管内释放多柔比星（Dox），实现了改善全身给药的多柔比星（Dox）在肿瘤外周和核心内的肿瘤内分布，LTSL是一种允许使用组织温度的轻度局部升高诱导脂质体药物释放的技术。拟议项目的目标是测试 使用新型超声成像回声LTSL（E-LTSL）进行均匀、严格控制的肿瘤内药物递送的创新方法的可行性和验证，该方法将允许基于图像引导药物递送（IGDD）的治疗。我们假设E-LTSL将允许实时控制和监测脂质体包裹的药物的释放。通过与使用高强度聚焦超声（HIFU）精确施加的局部热疗相结合，这将允许热诱导的脂质体药物释放，提供增强的肿瘤内药物递送到否则难以接近的肿瘤细胞。该概念基于我们在可生物降解LTSL合成及其在基于磁共振高强度聚焦超声的IGDD中的应用方面的专业知识。具体目的是：1、优化E-LTSL的体内外稳定性、释放度和成像性能. 2：使用小鼠模型确定E-LTSL介导的阿霉素体内递送、分布和功效。这项尖端的转化研究将增强我们俄克拉荷马州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，并将提供一种创新的途径，通过战略性地修改目前批准的疗法来改善癌症化疗的结果。

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.