Antiosteolytic Bisphosphonate Metallodrug Coordination Networks: Dissolution Profiles and In Vitro/In Vivo Toxicity...

Coordination compounds were synthesized and structurally characterized containing biocompatible alkaline earth metal ions and the bone-seeking agents clodronate (CLOD, (dichloromethanediyl)bis(phosphonate)) and medronate (MED, methylenediphosphonate). Dimensionality in these structures ranges from 0D (Mg-CLOD, Ca-CLOD) to 1D (Ca-CLOD-CP) to 2D (Ca-MED, Sr-CLOD). The salt Na₂-CLOD (used as a reference) and the CLOD coordination compounds with Mg²⁺, Ca²⁺, and Sr²⁺ were utilized as controlled release systems (excipient-containing tablets) of the active drug CLOD in acidic conditions that mimic the human stomach (pH = 1.3). Release of Ca²⁺ ions from the Ca-CLOD system was also monitored. The same experiments were carried out for the MED and Ca-MED systems. The drug release profiles were compared, and it was found that all Mg/Ca/Sr-containing compounds exhibit variable deceleration of the "active" CLOD release compared to the Na-containing reference. The calculated initial rates (μmol CLOD/min) followed the order Na (1.67) > Mg (1.32) > Sr (0.97) > Ca (0.81/0.70). The values were 1.44 and 0.57 for the MED and Ca-MED systems. This behavior was rationalized based on the structural idiosyncrasies of each system. The overall drug release profile for each system was the result of several structural factors, such as H-bonding interactions, strength of the metal-O(phosphonate) bonds, and packing density, but also crystal morphological/textural factors. These compounds were also tested for their toxicity at the concentration of 100 μM in vitro (micronucleus assay) and in vivo (brine shrimp Artemia salina) and were found to be of low toxicity.