Image-Guided Interventional Cancer Therapy with Liposomal Radionuclides

描述(申请人提供)：问题：通过静脉或口服输液向实体癌症输送药物通常效率低下，导致这些癌症的治疗结果不佳。克服这一困境的一种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。当治疗性放射性核素被用来代替药物时，由于β辐射的交叉作用，肿瘤内治疗的均质性得到了改善。目的：本研究的长期目标是：1)开发一种图像引导的肿瘤介入性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，以及介入性肿瘤内治疗的效果；2)开发一种用于该治疗的最佳治疗性放射性药物。这一建议的假设是，理想的脂质体放射性药物配方将被发现，以优化图像引导的癌症介入放射性核素治疗。具体目的是：1)确定不同表面电荷/大小以及靶向或不针对表皮生长因子受体(EGFR)的脂质体在瘤内的分布和滞留；2)确定186Re(Re-186)脂质体在裸鼠移植瘤中的治疗效果；3)采用剂量学方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：采用头颈部鳞状细胞癌(HNSCC)裸鼠移植瘤模型，对脂质体制剂进行检测。~(99m)Tc标记的非侵入性核成像将被用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的最佳脂质体配方的治疗效率。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学也将被研究。结果：在肿瘤内输注后，将更好地了解脂质体在肿瘤内滞留和分布的最佳特征。还将确定肿瘤内滞留和分布与肿瘤反应之间的关系。这将为将这种固体肿瘤疗法转化为人类提供关键的一步。好处：该项目将推动这一新的介入癌症治疗技术的使用，使实体癌患者受益。 公共卫生相关性：实体癌症治疗因向肿瘤提供的药物不足以确保肿瘤根除而受到极大影响。提议的新的实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输送到实体癌症。这种方法可能会提高肿瘤药物的浓度，从而改善肿瘤治疗，同时减少对正常组织的损害，从而使癌症患者受益。

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.