Image-Guided Interventional Cancer Therapy with Liposomal Radionuclides

描述（由申请人提供）：问题：通过静脉或口服输注给药实体癌症通常效率低下，导致这些癌症的治疗效果不佳。克服这一困境的新策略是使用图像引导的肿瘤内药物输注技术。然而，通过这种输注途径，实现均匀的肿瘤内药物分布是具有挑战性的。当使用治疗性放射性核素代替药物时，由于β辐射的交叉火力，肿瘤内治疗的均匀性得到改善。目的：本研究的长期目标是：1)建立图像引导的介入肿瘤脂质体放射性核素治疗系统，包括利用图像引导和剂量计划进行有效的肿瘤治疗，以及介入肿瘤内治疗的性能；2)开发一种最佳的治疗放射性药物。本建议的假设是理想的脂质体放射性药物配方将被发现用于优化图像引导的介入性癌症放射性核素治疗。具体目的是：1)确定肿瘤内输注后不同脂质体表面电荷/大小的分布和保留，以及是否特异性靶向表皮生长因子受体（EGFR）；2)测定铼-186 （Re-186）脂质体对裸鼠异种肿瘤移植的治疗效果；3)用剂量法测定携带治疗性放射性核素的脂质体的辐射吸收剂量分布。方法：脂质体制剂在裸鼠头颈部鳞状细胞癌异种移植模型中进行实验。使用锝-99m （Tc-99m）标记的脂质体进行无创核成像，以确定肿瘤内脂质体的保留和分布。携带治疗性放射性核素Re-186的最佳脂质体制剂的治疗效率也将被确定。肿瘤病理/组织化学将与卡尺测量的治疗反应及其对药物输送的潜在影响相关。作为开发有效的Re-186脂质体放射性药物的关键组成部分，Re-186脂质体在肿瘤和正常器官中的剂量测定也将进行研究。结果：将更好地了解肿瘤内输注后肿瘤内保留和分布的最佳脂质体特征。肿瘤内保留和分布与肿瘤反应之间的关系也将被确定。这将为将这种实体瘤疗法应用于人类提供关键的一步。益处：该项目将推进这种新的介入癌症治疗技术的应用，使实体癌患者受益。

DESCRIPTION (provided by applicant): Problem: Drug delivery to solid cancers via intravenous or oral infusion is generally inefficient, resulting in poor treatment outcomes for these cancers. An emerging strategy for overcoming this dilemma is the use of image- guided intratumoral drug infusion techniques. Yet, with this infusion route, achieving a homogeneous intratumoral drug distribution is challenging. When therapeutic radionuclides are used in place of drugs, homogeneity of the intratumoral therapy is improved due to the cross-fire of beta emissions. Purpose: The long-term goals of this research are: 1) to develop an image-guided interventional cancer liposomal radionuclide therapy system, which includes the use of image-guidance and dose planning for effective tumor therapy, and the performance of interventional intratumoral therapy; and 2) to develop an optimal therapeutic radiopharmaceutical for this therapy. The hypothesis of this proposal is that ideal liposome radiopharmaceutical formulations will be discovered for optimized image-guided interventional cancer radionuclide therapy. Specific Aims are: 1) to determine intratumoral distribution and retention of liposomes of various liposome surface charges / sizes and with / without specific targeting to epidermal growth factor receptor (EGFR) after intratumoral infusion; 2) to determine the therapeutic effectiveness of rhenium-186 (Re-186)-liposomes in tumor xenografts in nude rats; and 3) to determine radiation absorbed dose distribution using dosimetry for liposomes carrying therapeutic radionuclides. Methods: Liposome formulations will be tested in head and neck squamous cell carcinoma (HNSCC) xenograft model in nude rats. Non-invasive nuclear imaging with technetium-99m (Tc-99m)-labeled liposomes will be used to determine intratumoral retention and the distribution of liposomes within the tumor. Therapeutic efficiency of optimal liposome formulations carrying the therapeutic radionuclide, Re-186 will also be determined. Tumor pathology/histochemistry will be correlated with caliper measured therapy response and its potential influence on drug delivery. As a crucial component for development of an effective Re-186-liposome radiopharmaceutical, dosimetry of Re-186 liposomes in tumors and normal organs will also be studied. Outcomes: A better understanding of the optimal liposome characteristics for intratumoral retention and distribution following intratumoral infusion will be determined. The relationship between intratumoral retention and distribution and tumor response will also be determined. This will provide a crucial step for translation of this solid tumor therapy into humans. Benefits: This project will advance the use of this new interventional cancer therapy technique to benefit patients with solid cancers. Public Health Relevance: Solid cancer therapy is greatly compromised by insufficient drug delivery to tumors to ensure tumor eradication. The proposed new solid cancer therapy technique uses advanced medical imaging to guide the direct delivery of therapeutic radionuclides to the solid cancer. This method will potentially benefit cancer patients by enhancing tumor drug concentrations and thereby improving tumor therapy while decreasing damage to normal tissue.