Rice Samuel L, Muñoz Fernando Gómez, Benjamin Jamaal, Alnablsi Mhd Wisam, Pillai Anil, Osborne Joseph R, Beets-Tan Regina
Netherlands Cancer Institute-Antoni van Leeuwenhoekziekenhuis, Department of Radiology, Plesmanlaan 121, 1066 CX Amsterdam, Netherlands; UT Southwestern Medical Center, Department of Radiology, Interventional Radiology Section, 5959 Harry Hines Blvd., Dallas, TX 75390-9061, Professional Office Building I (HP6.600) Mail Code 8834, United States of America.
Netherlands Cancer Institute-Antoni van Leeuwenhoekziekenhuis, Department of Radiology, Plesmanlaan 121, 1066 CX Amsterdam, Netherlands.
Nucl Med Biol. 2024 Sep-Oct;136-137:108939. doi: 10.1016/j.nucmedbio.2024.108939. Epub 2024 Jul 2.
Great strides have been made identifying molecular and genetic changes expressed by various tumor types. These molecular and genetic changes are used as pharmacologic targets for precision treatment using large molecule (LM) proteins with high specificity. Theranostics exploits these LM biomolecules via radiochemistry, creating sensitive diagnostic and therapeutic agents. Intravenous (i.v.) LM drugs have an extended biopharmaceutical half-life thus resulting in an insufficient therapeutic index, permitting only palliative brachytherapy due to unacceptably high rates of systemic nontarget radiation doses to normal tissue. We employ tumor arteriole embolization isolating a tumor from the systemic circulation, and local intra-arterial (i.a.) infusion to improve uptake of a LM drug within a porcine renal tumor (RT).
In an oncopig RT we assess the in vivo biodistribution of Tc-labeled macroaggregated albumin (MAA) a surrogate for a LM theranostics agent in the RT, kidney, liver, spleen, muscle, blood, and urine. Control animals underwent i.v. infusion and experimental group undergoing arteriography with pseudovascular isolation (PVI) followed by direct i.a. injection.
Injected dose per gram (%ID/g) of the LM at 1 min was 86.75 ± 3.76 and remained elevated up to 120 min (89.35 ± 5.77) with i.a. PVI, this increase was statistically significant (SS) compared to i.v. (13.38 ± 1.56 and 12.02 ± 1.05; p = 0.0003 p = 0.0006 at 1 and 120 min respectively). The circulating distribution of LM in the blood was less with i.a. vs i.v. infusion (2.28 ± 0.31 vs 25.17 ± 1.84 for i.v. p = 0.033 at 1 min). Other organs displayed a trend towards less exposure to radiation for i.a. with PVI compared to i.v. which was not SS.
PVI followed by i.a. infusion of a LM drug has the potential to significantly increase the first pass uptake within a tumor. This minimally invasive technique can be translated into clinical practice, potentially rendering monoclonal antibody based radioimmunotherapy a viable treatment for renal tumors.
在识别各种肿瘤类型所表达的分子和基因变化方面已经取得了巨大进展。这些分子和基因变化被用作使用具有高特异性的大分子（LM）蛋白质进行精准治疗的药理学靶点。治疗诊断学通过放射化学利用这些LM生物分子，创造出灵敏的诊断和治疗剂。静脉内（i.v.）LM药物具有延长的生物制药半衰期，因此导致治疗指数不足，由于对正常组织的全身非靶向辐射剂量过高而不可接受，仅允许姑息性近距离放射治疗。我们采用肿瘤小动脉栓塞术将肿瘤与体循环隔离开，并进行局部动脉内（i.a.）灌注，以提高猪肾肿瘤（RT）内LM药物的摄取。
在一只患肾肿瘤的猪中，我们评估了锝标记的大颗粒白蛋白（MAA）（一种LM治疗诊断剂的替代物）在肾肿瘤、肾脏、肝脏、脾脏、肌肉、血液和尿液中的体内生物分布。对照组动物接受静脉内输注，实验组接受血管造影及假血管隔离（PVI），随后直接进行动脉内注射。
动脉内PVI组在1分钟时每克LM的注射剂量（%ID/g）为86.75±3.76，直至120分钟时仍保持在较高水平（89.35±5.77），与静脉内注射组（1分钟时为13.38±1.56，120分钟时为12.02±1.05）相比，这种增加具有统计学意义（SS）（1分钟和120分钟时p值分别为0.0003和0.0006）。与静脉内注射相比，动脉内注射时LM在血液中的循环分布较少（静脉内注射1分钟时为25.17±1.84，动脉内注射时为2.28±0.31，p = 0.033）。与静脉内注射相比，动脉内PVI组其他器官接受辐射的趋势较小，但无统计学意义。
PVI后动脉内注射LM药物有可能显著增加肿瘤内的首过摄取。这种微创技术可转化为临床实践，有可能使基于单克隆抗体的放射免疫疗法成为肾肿瘤的一种可行治疗方法。
