PET Enabled Microspheres for Radioembolization of Liver Tumors

描述（由申请人提供）： 项目摘要/摘要目前放射性栓塞Y-90微球已被普遍认为是治疗原发性和转移性肝肿瘤的最新技术。然而，由于缺乏用于剂量和治疗计划的准确诊断成像，以及在Y-90微球给药期间缺乏图像引导和剂量构象，临床结果差异很大。迄今为止的最佳实践是使用Tc 99 m标记的大分子聚集白蛋白（Tc 99 m-MAA）来模拟放射性栓塞Y-90微球的分布，用于筛选患者和剂量规划，并使用Y-90的韧致辐射或使用Y-90的极低内部对产生来定性评估仅在治疗后程序中给予的Y-90。研究人员建议，作为提高疗效的有利步骤，使微球PET可成像，以获得Y-90微球的最佳灵敏度和实时分布。仅含有PET同位素（即不含Y-90）的微球对于所有Y-90微球（包括当前的Therasphere（R）和SIR-Spheres（R））的患者筛查以及剂量和治疗规划来说是理想且无价的。用PET同位素和Y- 90包封的微球将使肿瘤的术中剂量递增，以提高安全性和有效性，以及术后监测和剂量确认。第一阶段研究的重点是用PET同位素制备微球，使用PET成像技术和其他补充成像技术准确地揭示它们的分布。具体目标是：（1）确定兼容的宿主基质和兼容的处理技术，用于创建用于剂量计划的PET使能微球和用于创建用于肝肿瘤放射性栓塞的PET使能Y-90微球;（2）为最佳PET图像提供足够水平的正电子发射体;（3）控制从微球的累积放射性泄漏至< 1%，以确保PET图像准确地表示Y-90微球的空间分布;以及（4）使用标准毒性筛选来评估初步的生物相容性。II期研究将从体内PET成像表征和体内生物相容性评估开始开始，并以使用PET使能微球进行患者筛选、剂量计划和Y-90微球对肿瘤的术中剂量递增的初步临床评估结束。 公共卫生相关性： 正电子发射微球（PET微球）的成功引入有可能通过定量和实时PET成像优化患者剂量规划和术中肿瘤剂量递增，显著提高放射性栓塞Y-90微球治疗肝脏原发性和转移性肿瘤的疗效。PET微球的使用有望通过更好地预测Y-90微球和实时监测Y-90微球的给药，提高Y-90微球治疗肝癌患者的安全性。可以早期检测到Y-90微球的意外分流，特别是过度栓塞和药物回流到胃肠道动脉中，并且可以在Y-90微球给药期间在术中采取纠正措施。本项目旨在确定将PET同位素和/或Y-90同位素包封（未标记）在定时生物可吸收微球中而无放射性同位素泄漏的可行性。不含Y-90的PET启用微球是当前放射性栓塞微球（Therasphere（R）或SIR-Spheres（R））的理想替代品，可用于最佳剂量和治疗计划，也是下一代Y-90微球的完美替代品，后者将包括用于定量成像的伴随PET放射性同位素。

DESCRIPTION (provided by applicant): Project Summary/Abstract Current radioembolic Y-90 microspheres have been generally recognized as the state-of-the-art for treating primary and metastatic liver tumors. However, the clinical results vary vastly due to the lack of accurate diagnostic imaging for dose and treatment planning, and the lack of image guidance and dose conformation during the administration of Y-90 microspheres. The best practice to date is to use Tc99m labeled macroaggregated albumin (Tc99m-MAA) to simulate the distribution of radioembolic Y-90 microspheres for screening patients and for dose planning and to use Bremsstrahlung radiation of Y-90 or to use the extremely low internal pair production of Y-90 to qualitatively assess the administered Y-90 only in a post-treatment procedure. The investigators propose, as the enabling step toward improving efficacy, to make microspheres PET imageable for the best sensitivity and real-time distribution of Y-90 microspheres. Microspheres with just PET isotopes (i.e. no Y-90) are ideal and invaluable for patient screening and dose and treatment planning for all Y-90 microspheres, including current Therasphere(R) and SIR-Spheres(R). Microspheres encapsulated with both PET isotopes and Y- 90 will enable intraoperative dose escalation to the tumors to enhance both safety and efficacy, and postoperative monitoring and dose confirmation. The Phase I research focuses on the preparation of microspheres with PET isotopes that accurately reveal their distribution using PET imaging techniques and other complimentary imaging techniques. The specific aims are to (1) identify compatible host matrices and compatible processing techniques for the creation of PET enabled microspheres for dose planning and for the creation of PET enabled Y-90 microspheres for radioembolization of liver tumors; (2) immobilize sufficient levels of positron emitters for optimal PET images; (3) control the cumulative radioactivity leakage from the microspheres to < 1% to ensure that PET images accurately represent the spatial distribution of Y-90 microspheres; and (4) assess preliminary biocompatibility using standard toxicity screening. The Phase II research will begin with in vivo PET imaging characterization and in vivo biocompatibility assessment and end with preliminary clinical assessment of using PET enabled microspheres for patient screening, dose planning, and intraoperative dose escalation of Y-90 microspheres to the tumors. PUBLIC HEALTH RELEVANCE: The successful introduction of positron emitting microspheres (PET microspheres) has the potential to dramatically improve the efficacy of radioembolic Y-90 microspheres for the treatment of primary and metastatic tumors in the liver by optimal patient dose planning and intraoperative dose escalation to the tumors through quantitative and real-time PET imaging. The use of PET microspheres is expected to improve the safety of Y-90 microspheres treatment of liver cancer patients through better prediction of Y-90 microspheres and real-time monitoring of the administration of Y-90 microspheres. Unexpected shunting of Y-90 microspheres and especially over-embolization with reflux of agent into gastrointestinal arteries can be detected early, and corrective actions can be taken intraoperatively during the administration of Y-90 microspheres. This project is to establish the feasibility of encapsulating (not labeling) PET isotopes and/or Y-90 isotopes in timed-bioabsorbable microspheres without radioisotope leakage. The PET enabled microspheres without Y-90 are ideal surrogates to current radioembolic microspheres (Therasphere(R) or SIR-Spheres(R)) for optimal dose and treatment planning and perfect surrogates to the next generation Y-90 microspheres, which will include companion PET radioisotopes for quantitative imaging.