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Potentiating Bisphosphonate-based Coordination Complexes to Treat Osteolytic Metastases


The hydrothermal reaction between bioactive metals (Ca2+, Zn2+, and Mg2+) salts and clinically utilized bisphosphonate, alendronate (ALEN), promotes the formation of several materials denominated as bisphosphonate-based coordination complexes (BPCCs). The systematic exploration of the effect of three variables M2+/ALEN molar ratio, temperature, and pH on the reaction yielded an unprecedented number of materials of enough crystal quality for structural elucidation. Five crystal structures were unveiled by X-ray diffraction (ALEN-Ca forms I and II, ALEN-Zn forms I and II, and ALEN-Mg) and their solid-state properties revealed in tandem with other techniques. The dissolution of these BPCCs was tested and contrasted to that of the commercially employed generic form of Fosamax® Alendronate Sodium, using fasted-state simulated gastric fluid and phosphate-buffered saline solution. Quantification of ALEN content was performed by derivatization with Cu2+, which produced a soluble complex suitable for quantification. Results show that these materials present a pH-dependent degradation. Moreover, a phase inversion temperature (PIT) nano-emulsion method was applied to the synthesis of ALEN-Ca form II. Size distribution analysis demonstrated the efficiency of the PIT-nano-emulsion method to decrease the particle size of this BPCC from ~60 µm to ~438 d.nm. The cytotoxicity of ALEN, ALEN-Ca form II (bulk crystals), and nano-Ca@ALEN (nanocrystals) against the MDA-MB-231 cell line was investigated. Nano-Ca@ALEN form II presents higher cytotoxicity effects than ALEN and ALEN-Ca form II (bulk crystals), showing inhibition of cell proliferation at 7.5 µM. These results provide evidence of the structure, stability, dissolution and cytotoxicity properties of ALEN-based BPCCs and pave the way for better formulation strategies for this drug through the design of nano-sized BPCCs for the treatment of bone-related diseases.

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Article information

29 Aug 2019
05 Feb 2020
First published
06 Feb 2020

J. Mater. Chem. B, 2020, Accepted Manuscript
Article type

Potentiating Bisphosphonate-based Coordination Complexes to Treat Osteolytic Metastases

G. Quiñones Vélez, L. Carmona-Sarabia, W. A. Rodríguez-Silva, A. A. Rivera Raíces, L. Feliciano-Cruz, C. T. Hu, E. A. Peterson and V. Lopez-Mejias, J. Mater. Chem. B, 2020, Accepted Manuscript , DOI: 10.1039/C9TB01857C

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