Li Ruth Gong, Lindland Kim, Tonstad Sandra Karen, Bønsdorff Tina Bjørnlund, Juzeniene Asta, Westrøm Sara, Larsen Roy Hartvig
Oncoinvent AS, 0484 Oslo, Norway.
Institute of Clinical Medicine, University of Oslo, 0316 Oslo, Norway.
Pharmaceutics. 2021 Apr 29;13(5):634. doi: 10.3390/pharmaceutics13050634.
Radium-224-labeled CaCO microparticles have been developed to treat peritoneal carcinomatosis. The microparticles function as carriers of Ra, facilitating intraperitoneal retention of the alpha-emitting radionuclide. It was necessary to control the size of microparticles in suspension over time and introduce a sterilization process for the clinical use of the radiopharmaceutical. Ethylenediamine tetra(methylene phosphonic acid) (EDTMP) was investigated as a stabilizing additive. The possibility of encapsulating the radiolabeled microparticles with an outer surface layer of CaCO for the improved retention of radioactivity by the carrier was studied. This work evaluated these steps of optimization and their effect on radiochemical purity, the biodistribution of radionuclides, and therapeutic efficacy. An EDTMP concentration of >1% (/) relative to CaCO stabilized the particle size for at least one week. Without EDTMP, the median particle size increased from ~5 µm to ~25 µm immediately after sterilization by autoclaving, and the larger microparticles sedimented rapidly in suspension. The percentage of adsorbed Ra progeny Pb increased from 56% to 94% at 2.4-2.5% (/) EDTMP when the Ra-labeled microparticles were layer-encapsulated. The improved formulation also resulted in a suitable biodistribution of radionuclides in mice, as well as a survival benefit for mice with intraperitoneal ovarian or colorectal tumors.
已研发出镭 - 224标记的碳酸钙微粒用于治疗腹膜癌。这些微粒作为镭的载体，有助于α发射放射性核素在腹腔内的滞留。有必要随时间控制悬浮液中微粒的大小，并为该放射性药物的临床应用引入灭菌工艺。研究了乙二胺四（亚甲基膦酸）（EDTMP）作为一种稳定添加剂。研究了用碳酸钙外层包裹放射性标记微粒以提高载体对放射性的保留的可能性。这项工作评估了这些优化步骤及其对放射化学纯度、放射性核素生物分布和治疗效果的影响。相对于碳酸钙，EDTMP浓度>1%（/）可使粒径稳定至少一周。没有EDTMP时，通过高压灭菌消毒后，中位粒径立即从约5 µm增加到约25 µm，并且较大的微粒在悬浮液中迅速沉降。当镭标记的微粒进行层包裹时，在2.4 - 2.5%（/）的EDTMP下，吸附的镭子代铅的百分比从56%增加到94%。改进后的制剂还导致放射性核素在小鼠体内有合适的生物分布，以及对患有腹腔内卵巢或结肠肿瘤的小鼠有生存益处。
