Kirakci Kaplan, Pozmogova Tatiana N, Protasevich Andrey Y, Vavilov Georgy D, Stass Dmitri V, Shestopalov Michael A, Lang Kamil
Institute of Inorganic Chemistry of the Czech Academy of Sciences, ŘeŽ 1001, 250 68 Husinec-ŘeŽ, Czech Republic.
SPF-vivarium, Institute of Cytology and Genetics, SB RAS, 10 Acad. Lavrentieva ave., 630090, Novosibirsk, Russia and Novosibirsk State University, 1 Pirogova st., 630090, Novosibirsk, Russia.
Biomater Sci. 2021 Apr 21;9(8):2893-2902. doi: 10.1039/d0bm02005b. Epub 2021 Jan 19.
X-ray-induced photodynamic therapy (X-PDT) has recently evolved into a suitable modality to fight cancer. This technique, which exploits radiosensitizers producing reactive oxygen species, allows for a reduction of the radiation dose needed to eradicate cancer in the frame of the radiotherapy treatment of deep tumors. The use of transition metal complexes able to directly produce singlet oxygen, O(Δ), upon X-ray irradiation constitutes a promising route towards the optimization of the radiosensitizer's architecture. In our endeavour to conceive pertinent agents for X-PDT, we designed an octahedral molybdenum cluster complex (Mo) with iodine inner ligands, and carboxylated apical ligands bearing ethylene oxide organic functions. The sodium salt of this complex is highly soluble in aqueous media and displays red luminescence which is efficiently quenched by oxygen to produce O(Δ) in a high quantum yield. Furthermore, due to its high radiodensity, the complex exhibits radioluminescence in aqueous media, with the same spectral features as for photoluminescence, indicating the production of O(Δ) upon X-ray irradiation. The uptake of the complex by Hep-2 and MRC-5 cells is negligible during the first hours of incubation, then considerably increases in connection with the hydrolysis of the apical ligands. The complex exhibits low toxicity in vitro and induces a radiotoxic effect, noticeable against cancerous Hep-2 cells but negligible against normal MRC-5 cells, at X-ray doses that do not affect cell viability otherwise. The first evaluation of in vivo toxicity of an Mo complex on a mouse model evidences a moderate and delayed toxic effect on kidneys, with an intravenous LD value of 390 ± 30 mg kg, possibly connected with hydrolysis-induced aggregation of the complex. Overall, this complex displays attractive features as a singlet oxygen radiosensitizer for X-PDT, highlighting the potential of transition metal cluster complexes towards this modality.
X射线诱导光动力疗法（X-PDT）最近已发展成为一种治疗癌症的合适方法。该技术利用能产生活性氧的放射增敏剂，在深部肿瘤的放射治疗中，可减少根除癌症所需的辐射剂量。使用在X射线照射下能直接产生单线态氧O(Δ)的过渡金属配合物，是优化放射增敏剂结构的一条有前景的途径。为了设计出适用于X-PDT的相关试剂，我们设计了一种八面体钼簇配合物（Mo），其内部配体为碘，顶端配体为带有环氧乙烷有机官能团的羧基化配体。该配合物的钠盐在水性介质中高度可溶，并呈现红色发光，氧气能有效猝灭这种发光，从而以高量子产率产生O(Δ)。此外，由于其高辐射密度，该配合物在水性介质中表现出放射发光，其光谱特征与光致发光相同，表明在X射线照射下会产生O(Δ)。在孵育的最初几个小时内，Hep-2细胞和MRC-5细胞对该配合物的摄取可忽略不计，随后随着顶端配体的水解，摄取量显著增加。该配合物在体外表现出低毒性，并在不影响细胞活力的X射线剂量下诱导放射毒性作用，对癌细胞Hep-2细胞明显，但对正常MRC-5细胞可忽略不计。对一种钼配合物在小鼠模型上进行的体内毒性首次评估表明，对肾脏有中度且延迟的毒性作用，静脉注射半数致死量值为390±30 mg/kg，这可能与配合物水解诱导的聚集有关。总体而言，该配合物作为X-PDT的单线态氧放射增敏剂具有吸引人的特性，突出了过渡金属簇配合物在这种治疗方法中的潜力。
