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

描述：癌症化疗采用全身给药，特异性有限，在正常组织中引起毒副作用，药物效率低/不足。 传递到肿瘤细胞，导致复发。为了解决这些问题，人们开发了脂质体隐形给药系统(如Doxil)，以选择性地在肿瘤内蓄积，从而在减少药物暴露和对正常组织的毒性的同时，增强了肿瘤内的药物输送能力。然而，现有的临床批准的纳米载体只在肿瘤的血管周围空间释放有效载荷，阻止或阻止分布到肿瘤核心中灌流不良的远程细胞，这些细胞导致耐药和肿瘤复发。因此，到目前为止，通过隐形脂质体技术实现的肿瘤导向剂量递增尚未改善治疗效果。为了克服这些限制，我们研究的长期目标是优化和提供统一的抗肿瘤药物实时控制的瘤内给药， 从而为医生提供更精确的剂量控制。在初步研究中，我们通过从低温敏感脂质体(LTSL)诱导血管内快速释放多柔比星(Dox)，实现了系统给药阿霉素(Dox)在肿瘤周围和核心内的改善分布，这是一种允许利用组织温度的温和局部升高来诱导脂质体药物释放的技术。拟议项目的目标是测试 使用新颖的超声可成像回声LTSL(E-LTSL)，实现基于图像引导的药物传递(IGDD)治疗，实现均质、严格控制的抗肿瘤药物内传递的创新方法的可行性和有效性。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。与高强度聚焦超声(HIFU)精确应用的局部热疗相结合，这将允许热诱导脂质体药物释放，为原本无法接触到的肿瘤细胞提供增强的肿瘤内药物输送。这一概念建立在我们在可生物降解LTSL合成及其在磁共振-高强度聚焦超声IGDD中的应用方面的专业知识的基础上。具体目标为：1：优化E-LTSL的体内外稳定性、释放性和形象性。2.以小鼠为模型，研究E-LTSL介导的阿霉素在体内的传递、分布和药效。这项尖端的转化研究将增强我们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，并将提供一条通过战略性修改目前批准的疗法来改善癌症化疗结果的创新途径。

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.