Specificity of Growth Inhibitors and their Cooperative Effects in Calcium Oxalate Monohydrate Crystallization

Abstract

The molecular recognition and interactions governing site-specific adsorption of growth inhibitors on crystal surfaces can be tailored in order to control the anisotropic growth rates and physical properties of crystalline materials. Here we examine this phenomenon in calcium oxalate monohydrate (COM) crystallization, a model system of calcification with specific relevance for pathological mineralization. We analyzed the effect of three putative growth inhibitors--chondroitin sulfate, serum albumin, and transferrin--using analytical techniques capable of resolving inhibitor-crystal interactions from interfacial to bulk scales. We observed that each inhibitor alters surface growth by adsorbing on to distinct steps emanating from screw dislocations on COM surfaces. Binding of inhibitors to different crystallographic faces produced morphological modifications that are consistent with classical mechanisms of layer-by-layer crystal growth inhibition. The site-specific adsorption of inhibitors on COM surfaces was confirmed by bulk crystallization, fluorescent confocal microscopy, and atomic force microscopy. Kinetic studies of COM growth at varying inhibitor concentrations revealed marked differences in their efficacy and potency. Systematic analysis of inhibitor combinations, quantified via the combination index, identified various binary pairings capable of producing synergistic, additive, and antagonistic effects. Collectively, our investigation of physiologically relevant biomolecules suggests potential roles of COM inhibitors in pathological crystallization and provides guiding principles for biomimetic design of molecular modifiers for applications in crystal engineering.

Antimalarials inhibit hematin crystallization by unique drug–surface site interactions

“…2 and 3). Discrepancies between the inhibitor concentrations needed to arrest step growth observed by AFM and those that suppress the growth of crystals in a bulk crystallization experiment are common in the crystallization literature (56,61,62). Several processes may contribute to this disparity.…”

Structural analysis of metal-doped calcium oxalate

“…[20][21][22] Research that led to the identification of organic modifiers as growth inhibitors of calcium oxalate 23,24 attracted the attention of scientists because of its potential relevance for pharmaceutical development and crystal engineering. Nevertheless, relatively few studies have demonstrated the incorporation of metals into synthetic calcium oxalates, as shown, for example, in the case of Sr 2+ .…”

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