Instituto de Ciências Biomédicas Abel Salazar, R. Jorge de Viterbo Ferreira 228, 4050-313 Porto, Portugal.
LAQV-REQUIMTE, Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, Campus de Caparica, 2829-516 Caparica, Portugal.
Int J Pharm. 2021 Dec 15;610:121262. doi: 10.1016/j.ijpharm.2021.121262. Epub 2021 Nov 5.
Bisphosphonates are a class of drugs widely used for the treatment of several pathologies associated with increased bone resorption. Although displaying low oral bioavailability, these drugs have the ability to accumulate in bone matrix, where the biological effects are exerted. In the present work, four mono- and dianionic Etidronate-based Organic Salts and Ionic Liquids (Eti-OSILs) were developed by combination of this drug with the superbases 1,1,3,3-tetramethylguanidine (TMG) and 1,5-diazabicyclo(4.3.0)non-5-ene (DBN) as cations, aiming to improve not only the physicochemical properties of this seminal bisphosphonate, but also its efficacy in the modulation of cellular behavior, particularly on human osteoclasts and osteoblasts. It was observed that some of the developed compounds, in particular the dianionic ones, presented very high water solubility and diminished or absent polymorphism. Also, several of them appeared to be more cytotoxic against human breast and osteosarcoma cancer cell lines while retaining low toxicity to normal cells. Regarding bone cells, a promotion of an anabolic state was observed for all Eti-OSILs, primarily for the dianionic ones, which leads to an inhibition of osteoclastogenesis and an increase in osteoblastogenesis. The observed effects resulted from differential modulation of intracellular signaling pathways by the Eti-OSILs in comparison with Etidronate. Hence, these results pave the way for the development of more efficient and bioavailable ionic formulations of bisphosphonates aiming to effectively modulate bone metabolism, particularly in the case of increased bone resorption.
双膦酸盐是一类广泛用于治疗多种与骨吸收增加相关疾病的药物。尽管口服生物利用度较低，但这些药物能够在骨基质中积累，从而发挥其生物学效应。在本工作中，通过将该药物与超强碱 1,1,3,3-四甲基胍（TMG）和 1,5-二氮杂二环[4.3.0]壬-5-烯（DBN）组合，开发了四种单阴离子和二阴离子依替膦酸盐基有机盐和离子液体（Eti-OSILs），旨在不仅改善这种开创性双膦酸盐的物理化学性质，而且提高其调节细胞行为的功效，特别是对人破骨细胞和成骨细胞。结果表明，一些开发的化合物，特别是二阴离子化合物，具有非常高的水溶性和降低或不存在多晶型性。此外，其中一些化合物对人乳腺癌和骨肉瘤癌细胞系的细胞毒性似乎更高，而对正常细胞的毒性较低。关于骨细胞，所有 Eti-OSILs 均观察到促进合成代谢状态，主要是二阴离子化合物，其导致破骨细胞生成减少和成骨细胞生成增加。与依替膦酸盐相比，Eti-OSILs 通过对细胞内信号通路的差异调节，导致了观察到的作用。因此，这些结果为开发更有效和生物利用的双膦酸盐离子制剂铺平了道路，旨在有效调节骨代谢，特别是在骨吸收增加的情况下。
