Novel ¹⁸⁸Re multi-functional bone-seeking compounds: Synthesis, biological and radiotoxic effects in metastatic breast cancer cells

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• 作者：Cé ; lia Fernandes ; ^{celiaf@ctn.ist.utl.pt" class="auth_mail" title="E-mail the corresponding author} ; Sofia Monteiro ; Ana Belchior ; Fernanda Marques ; Lurdes Gano ; Joã ; o D.G. Correia ; Isabel Santos
• 关键词：Bisphosphonates ; Bone pain palliation ; Radiocytotoxic effects ; Radiopharmaceuticals ; Rhenium-188 ; Systemic radiotherapy
• 刊名：Nuclear Medicine and Biology
• 出版年：2016
• 出版时间：February 2016
• 年：2016
• 卷：43
• 期：2
• 页码：150-157
• 全文大小：721 K

文摘

Radiolabeled bisphosphonates (BPs) have been used for bone imaging and delivery of β⁻ emitting radionuclides for bone pain palliation. As a β⁻ emitter, ¹⁸⁸Re has been considered particularly promising for bone metastases therapy. Aimed at finding innovative bone-seeking agents for systemic radiotherapy of bone metastases, we describe herein novel organometallic compounds of the type fac-[¹⁸⁸Re(CO)₃(k³-L)], (L = BP-containing chelator), their in vitro and in vivo stability, and their cellular damage in MDAMB231 cells, a metastatic breast cancer cell line.

Methods

After synthesis and characterization of the novel organometallic compounds of the type fac-[¹⁸⁸Re(CO)₃(k³-L)] their radiochemical purity and in vitro stability was assessed by HPLC. In vivo stability and pharmacokinetic profile were evaluated in mice and the radiocytotoxic activity and DNA damage were assessed by MTT assay and by the cytokinesis-block micronucleus (CBMN) assay, respectively.

Results

Among all complexes, ¹⁸⁸Re3 was obtained with high radiochemical purity (> 95%) and high specific activity and presented high in vitro and in vivo stability. Biodistribution studies of ¹⁸⁸Re3 in Balb/c mice showed fast blood clearance, high bone uptake (16.1 ± 3.3% IA/g organ, 1 h p.i.) and high bone-to-blood and bone-to-muscle radioactivity ratios, indicating that it is able to deliver radiation to bone in a very selective way. The radiocytotoxic effect elicited by ¹⁸⁸Re3 in the MDAMB231 cells was dependent on its concentration, and was higher than that induced by identical concentrations of [¹⁸⁸ReO₄]⁻. Additionally, ¹⁸⁸Re3 elicited morphological changes in the cells and induced DNA damage by the increased number of MN observed.

Conclusion

Altogether, our results demonstrate that ¹⁸⁸Re3 could be considered an attractive candidate for further preclinical evaluation for systemic radionuclide therapy of bone metastases considering its ability to deliver radiation to bone in a very selective way and to induce radiation damage.