Novel Radionuclide Cancer Therapy using Radiolabeled Nanoparticles

我们已经通过使用包封放射性核素的脂质体获得了高的肿瘤蓄积，因此，我们认为本研究的最重要任务是不让放射性核素在正常组织中蓄积，如肝、脾或骨髓。我们开发了一种放射性标记方法，该方法将允许脂质体包封足够量的^<186>Re/^<188>Re和^<90>Y，它们是用于放射治疗的合适核素。对于这种方法，我们新制备了亲脂性螯合剂MRP 20和亲水性螯合剂亚乙基二半胱氨酸（CD）。标记方法和配体的选择是非常重要的，因为它们可能在很大程度上影响正常组织中的非特异性积累，如下所述。使用载体如脂质体或脂质球允许精细控制放射性核素的生物分布。在脂质体的情况下，它大量积聚在肿瘤中，也在肝脏和脾脏中，然后在那里释放放射性核素。释放核素的跟随行为 ...更多信息 主要由它们的螯合配体控制。从对亚细胞分布的详细检查结果可以清楚地看出，^<67>Ga和^<111>In（也可能是^<90>Y）由于其自身的性质而从胞质溶胶转移到溶酶体并在那里停留很长时间，然而，与高亲和力配体的螯合显著地改变了它们的行为。核素-配体复合物存在于胞质溶胶中并离开细胞。这些结果表明，高亲和力的配体对于减少正常组织的放射性暴露是必不可少的，并进一步表明配体设计，如通过膜转运蛋白的排泄，可能使其主动清除正常组织中的放射性核素成为可能.尝试了体外刺激响应型药物载体的制备。通过扣动“扳机”，破坏血液循环中的载体，并随后释放出放射性核素。虽然已经取得了一些有希望的结果，但是对载体的修饰导致了肿瘤积聚的大大减少。进一步的检查正在进行中。少

We have already obtained high tumor accumulation by using radionuclide-encapsulating liposomes, therefore, we consider that the most important task of this research is not to allow radionuclides accumulate in normal tissues, such as liver, spleen, or bone marrow.1. We developed a radiolabelling method that will permit liposomes encapsulate enough amount of ^<186>Re/^<188>Re and ^<90>Y, which are suitable nuclides for radiotherapy. For this method, we newly prepared MRP20, a lipophilic chelating agent, and ethylenedicysteine (CD), a hydrophilic one. Labeling methods and choice of ligand are very important, because they may largely affect non-specific accumulation in normal tissues as described below.2. Use of carriers such as liposomes or lipid spheres permitted fine control of radionuclide biodistribution. In case of liposomes, it accumulated in the tumor in large quantity and also in the liver and spleen, and then released radionuclides there. Following behavior of released-nuclides w … More as dominated by their chelating ligands. From results of detailed examination on subcellular distribution, it was cleared that ^<67>Ga and ^<111>In (maybe also ^<90>Y) transferred from cytosol to lysosome and remained there for a long time owing to their own nature, however, chelation to high-affinity ligands dramatically altered their behavior. Nuclide-ligand complexes were present in cytosol and went out of the cell. These results suggest that high-affinity ligands are essential for reduction of radiation exposure to normal tissues, and further suggested that ligand design, such as leading of excretion by membrane transporter, may make it possible to remove radionuclides in normal tissues actively.3. Preparation of external stimulus-responsible drug carrier was tried. By pulling the "trigger", destruction of carriers in the blood circulation and following release encapsulated-radionuclides were planed. Some promising results have been obtained, however, modification of carriers led to decrease tumor accumulation largely. Further examinations are under way. Less