PDF(Pubmed)
Abstract：
Targeted alpha therapy (TAT) relies on chemical affinity or active targeting using radioimmunoconjugates as strategies to deliver α-emitting radionuclides to cancerous tissue. These strategies can be affected by transmetalation of the parent radionuclide by competing ions in vivo and the bond-breaking recoil energy of decay daughters. The retention of α-emitting radionuclides and the dose delivered to cancer cells are influenced by these processes. Encapsulating α-emitting radionuclides within nanoparticles can help overcome many of these challenges. Poly(lactic-co-glycolic acid) (PLGA) nanoparticles are a biodegradable and biocompatible delivery platform that has been used for drug delivery. In this study, PLGA nanoparticles are utilized for encapsulation and retention of actinium-225 ([225Ac]Ac3+). Encapsulation of [225Ac]Ac3+ within PLGA nanoparticles (Zave = 155.3 nm) was achieved by adapting a double-emulsion solvent evaporation method. The encapsulation efficiency was affected by both the solvent conditions and the chelation of [225Ac]Ac3+. Chelation of [225Ac]Ac3+ to a lipophilic 2,9-bis-lactam-1,10-phenanthroline ligand ([225Ac]AcBLPhen) significantly decreased its release (< 2%) and that of its decay daughters (< 50%) from PLGA nanoparticles. PLGA nanoparticles encapsulating [225Ac]AcBLPhen significantly increased the delivery of [225Ac]Ac3+ to murine (E0771) and human (MCF-7 and MDA-MB-231) breast cancer cells with a concomitant increase in cell death over free [225Ac]Ac3+ in solution. These results demonstrate that PLGA nanoparticles have potential as radionuclide delivery platforms for TAT to advance precision radiotherapy for cancer. In addition, this technology offers an alternative use for ligands with poor aqueous solubility, low stability, or low affinity, allowing them to be repurposed for TAT by encapsulation within PLGA nanoparticles.
摘要：
靶向α治疗(TAT)依赖于使用放射免疫缀合物的化学亲和力或主动靶向作为将α发射放射性核素递送至癌组织的策略。这些策略可能会受到母体放射性核素通过体内竞争离子和衰变子体的键断裂反冲能量的金属转移的影响。α发射放射性核素的保留和递送至癌细胞的剂量受这些过程的影响。将α发射放射性核素封装在纳米颗粒内可以帮助克服许多这些挑战。聚(乳酸-共-乙醇酸)(PLGA)纳米颗粒是已用于药物递送的可生物降解且生物相容的递送平台。在这项研究中,PLGA纳米颗粒被用于包封和保留act-225([225Ac]Ac3+)。[225Ac]Ac3+在PLGA纳米颗粒(Zave=155.3nm)内的包封是通过采用双乳液溶剂蒸发方法实现的。包封效率受溶剂条件和[225Ac]Ac3的螯合作用的影响。[225Ac]Ac3+与亲脂性2,9-双内酰胺-1,10-菲咯啉配体([225Ac]AcBLPhen)的螯合显著降低了其从PLGA纳米颗粒的释放(<2%)和其衰变子体(<50%)。包封[225Ac]AcBLPhen的PLGA纳米颗粒显著增加了[225Ac]Ac3+向鼠(E0771)和人(MCF-7和MDA-MB-231)乳腺癌细胞的递送,与溶液中的游离[225Ac]Ac3+相比,细胞死亡伴随增加。这些结果证明PLGA纳米颗粒具有作为TAT的放射性核素递送平台以推进癌症的精确放射治疗的潜力。此外,该技术为水溶性差的配体提供了替代用途，稳定性低,或低亲和力，允许它们通过封装在PLGA纳米颗粒中而被重新用于TAT。
