Ancira-Cortez A, Ferro-Flores G, Jiménez-Mancilla N, Morales-Avila E, Trujillo-Benítez D, Ocampo-García B, Santos-Cuevas C, Escudero-Castellanos A, Luna-Gutiérrez M
Departamento de Materiales Radiactivos, Instituto Nacional de Investigaciones Nucleares, Estado de México 52750, Mexico; Facultad de Química, Universidad Autónoma del Estado de México, Estado de México 50180, Mexico.
Departamento de Materiales Radiactivos, Instituto Nacional de Investigaciones Nucleares, Estado de México 52750, Mexico.
Mater Sci Eng C Mater Biol Appl. 2020 Dec;117:111335. doi: 10.1016/j.msec.2020.111335. Epub 2020 Aug 7.
Among the nanomaterials, rare sesquioxides (lanthanide oxides such as LuO) are of interest due to their adequate thermal conductivity, excellent chemical stability, and high light output. The prostate-specific membrane antigen (PSMA) is an integral multifunctional protein overexpressed in various types of cancer cells. The radiolabeled PSMA inhibitor peptides (iPSMA) have demonstrated their usefulness as specific probes in the treatment and detection of a wide variety of neoplasms, mainly due to their high in vivo recognition by the PSMA protein. The objective of this research was to synthesize LuO-iPSMA nanoparticles (NPs) and characterize their physicochemical properties before and after neutron activation, as well as to assess their biodistribution profile and in vitro potential to target cells overexpressing PSMA. The LuO NPs were synthesized by the precipitation-calcination method and conjugated to the iPSMA peptide using DOTA (1,4,7,10-tetraazocyclodecane-N,N',N″,N‴-tetraacetic acid) as a linking agent. Results of the physicochemical characterization by FT-IR and UV-Vis spectroscopies, SEM, TEM, DLS, HRTEM, SAED, DSC-TGA, and X-ray diffraction indicated the formation of LuO-iPSMA NPs (diameter of 29.98 ± 9.07 nm), which were not affected in their physicochemical properties after neutron activation. LuO-iPSMA NPs showed high affinity (K = 5.7 ± 1.9 nM) for the PSMA protein, evaluated by the saturation assay on HepG2 hepatocellular carcinoma cells (PSMA-positive). The biodistribution profile of the nanosystem in healthy mice showed the main uptake in the liver. After irradiation, radioactive LuO-iPSMA NPs exhibited radioluminescent properties, making the in vivo acquisition of their biodistribution, via optical imaging, possible. The results obtained from this research validate the execution of additional preclinical studies with the objective of evaluating the potential of the LuO-iPSMA NPs for the targeted radiotherapy and in vivo imaging of tumors overexpressing the PSMA protein.
在纳米材料中，稀土倍半氧化物（如镥氧化物LuO）因其具有足够的热导率、出色的化学稳定性和高光输出而备受关注。前列腺特异性膜抗原（PSMA）是一种在各种癌细胞中过度表达的整合多功能蛋白。放射性标记的PSMA抑制剂肽（iPSMA）已证明其作为特异性探针在多种肿瘤的治疗和检测中的有用性，这主要归因于它们在体内被PSMA蛋白高度识别。本研究的目的是合成LuO-iPSMA纳米颗粒（NPs），并表征其在中子活化前后的物理化学性质，以及评估其生物分布概况和体外靶向过表达PSMA细胞的潜力。通过沉淀-煅烧法合成LuO NPs，并使用DOTA（1,4,7,10-四氮杂环十二烷-N,N',N″,N‴-四乙酸）作为连接剂将其与iPSMA肽偶联。通过傅里叶变换红外光谱（FT-IR）、紫外可见光谱（UV-Vis）、扫描电子显微镜（SEM）、透射电子显微镜（TEM）、动态光散射（DLS）、高分辨率透射电子显微镜（HRTEM）、选区电子衍射（SAED）、差示扫描量热法-热重分析法（DSC-TGA）和X射线衍射进行的物理化学表征结果表明形成了LuO-iPSMA NPs（直径为29.98±9.07 nm），其物理化学性质在中子活化后未受影响。通过对HepG2肝癌细胞（PSMA阳性）进行饱和测定评估，LuO-iPSMA NPs对PSMA蛋白显示出高亲和力（K = 5.7±1.9 nM）。纳米系统在健康小鼠中的生物分布概况显示主要摄取部位在肝脏。辐照后，放射性LuO-iPSMA NPs表现出放射发光特性，使得通过光学成像在体内获取其生物分布成为可能。本研究获得的结果验证了开展额外临床前研究的可行性，其目的是评估LuO-iPSMA NPs在靶向放疗和过表达PSMA蛋白肿瘤的体内成像方面的潜力。
