Image-Guided Interventional Cancer Therapy with Liposomal Radionuclides

描述（由申请人提供）：问题：通过静脉内或口服输注向实体癌递送药物通常效率低下，导致这些癌症的治疗结果不佳。一种克服这种困境的新兴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发射的交叉火力，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）开发一种图像引导的介入性肿瘤脂质体放射性核素治疗系统，包括使用图像引导和剂量规划进行有效的肿瘤治疗，以及进行介入性肿瘤内治疗; 2）开发用于这种治疗的最佳治疗放射性药物。该建议的假设是，将发现理想的脂质体放射性药物制剂用于优化的图像引导的介入性癌症放射性核素治疗。具体目标是：1）确定肿瘤内输注后各种脂质体表面电荷/尺寸的脂质体的肿瘤内分布和保留，并且具有/不具有对表皮生长因子受体（EGFR）的特异性靶向; 2）确定在裸大鼠中肿瘤异种移植物中Re-186（Re-186）-脂质体的治疗有效性;和3）使用剂量测定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：将在裸大鼠头颈部鳞状细胞癌（HNSCC）异种移植模型中测试脂质体制剂。将使用锝-99m（Tc-99 m）标记脂质体的非侵入性核成像来确定肿瘤内滞留和脂质体在肿瘤内的分布。还将确定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。肿瘤病理学/组织化学将与卡尺测量的治疗反应及其对药物递送的潜在影响相关。作为开发有效的Re-186-脂质体放射性药物的重要组成部分，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。成果：更好地了解肿瘤内输注后肿瘤内滞留和分布的最佳脂质体特性。还将确定肿瘤内滞留和分布与肿瘤缓解之间的关系。这将为将这种实体瘤疗法转化为人类提供关键的一步。受益：该项目将促进这种新的介入性癌症治疗技术的使用，使实体癌患者受益。 公共卫生相关性：固体癌症治疗由于药物输送不足而大大削弱，无法确保肿瘤根除。所提出的新的固体癌症治疗技术使用先进的医学成像来引导治疗性放射性核素直接递送到固体癌症。这种方法通过提高肿瘤药物浓度，从而改善肿瘤治疗，同时减少对正常组织的损伤，将潜在地使癌症患者受益。

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.