Qin Yun, Imobersteg Stefan, Blanc Alain, Frank Stephan, Schibli Roger, Béhé Martin P, Grzmil Michal
Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institute, 5232 Villigen, Switzerland.
Department of Chemistry and Applied Biosciences, ETH Zurich, 8093 Zurich, Switzerland.
Pharmaceutics. 2020 Nov 12;12(11):1088. doi: 10.3390/pharmaceutics12111088.
The overexpression of cholecystokinin B receptor (CCKBR) in human cancers led to the development of radiolabeled minigastrin analogues for targeted radionuclide therapy, which aims to deliver cytotoxic radiation specifically to cancer cells. Alpha emitters (e.g., actinium-225) possess high potency in cancer cell-killing and hold promise for the treatment of malignant tumors. In these preclinical studies, we developed and evaluated CCKBR-targeted alpha particle therapy. The cellular uptake and cytotoxic effect of actinium-225 labeled and HPLC-purified minigastrin analogue [Ac]Ac-PP-F11N were characterized in the human squamous cancer A431 cells transfected with CCKBR. Nude mice bearing A431/CCKBR tumors were used for biodistribution and therapy studies followed by histological analysis and SPECT/CT imaging. In vitro, [Ac]Ac-PP-F11N showed CCKBR-specific and efficient internalization rate and potent cytotoxicity. The biodistribution studies of [Ac]Ac-PP-F11N revealed CCKBR-specific uptake in tumors, whereas the therapeutic studies demonstrated dose-dependent inhibition of tumor growth and extended mean survival time, without apparent toxicity. The histological analysis of kidney and stomach indicated no severe adverse effects after [Ac]Ac-PP-F11N administration. The post-therapy SPECT-CT images with [In]In-PP-F11N confirmed no CCKBR-positive tumor left in the mice with complete remission. In conclusion, our study demonstrates therapeutic efficacy of [Ac]Ac-PP-F11N without acute radiotoxicity in CCKBR-positive cancer model.
胆囊收缩素B受体（CCKBR）在人类癌症中的过表达促使了用于靶向放射性核素治疗的放射性标记小胃泌素类似物的研发，其目的是将细胞毒性辐射特异性地传递至癌细胞。α发射体（如锕-225）在杀死癌细胞方面具有高效能，有望用于治疗恶性肿瘤。在这些临床前研究中，我们研发并评估了CCKBR靶向的α粒子疗法。在转染了CCKBR的人鳞状癌A431细胞中，对锕-225标记并经高效液相色谱纯化的小胃泌素类似物[Ac]Ac-PP-F11N的细胞摄取和细胞毒性作用进行了表征。将荷A431/CCKBR肿瘤的裸鼠用于生物分布和治疗研究，随后进行组织学分析和单光子发射计算机断层扫描/计算机断层扫描（SPECT/CT）成像。在体外，[Ac]Ac-PP-F11N表现出CCKBR特异性且高效的内化率以及强大的细胞毒性。[Ac]Ac-PP-F11N的生物分布研究显示肿瘤中有CCKBR特异性摄取，而治疗研究表明其对肿瘤生长有剂量依赖性抑制作用，并延长了平均生存时间，且无明显毒性。肾脏和胃部的组织学分析表明，给予[Ac]Ac-PP-F11N后未出现严重不良反应。用[In]In-PP-F11N进行治疗后的SPECT-CT图像证实，完全缓解的小鼠体内没有留下CCKBR阳性肿瘤。总之，我们的研究证明了[Ac]Ac-PP-F11N在CCKBR阳性癌症模型中具有治疗效果且无急性放射毒性。
