(656b) Modifiers of Calcium Oxalate Monohydrate Crystallization: Tailoring Modifier–Crystal Interactions for Rational Drug Design

Bryan G. Alamani, Jihae Chung, and Jeffrey D. Rimer

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Chemical and Biomolecular Engineering, University of Houston, Houston, TX, 77204 USA

Calcium oxalate monohydrate (COM) is a major constituent of kidneys stones. Current therapeutics block solute (Ca²⁺ and C₂O₄^2-) attachment to crystals through either complexation in solution or binding to specific sites on crystal surfaces.¹ Despite advancements in drug design, the incidence rate of stones is on the rise, thus emphasizing the need for alternative therapies. When designing new modifiers as drugs, it is important to consider the underlying fundamental physical interactions of modifiers (ions or molecules) with COM crystal surfaces. These interactions may be elucidated through a combination of experimental and theoretical studies. In this talk, we will describe systematic studies of bulk crystallization and in situ characterization of surface growth in the presence and absence of modifiers.² We have explored the effect of metal ions (both monovalent and divalent), small organics, and native proteins that are commonly observed in human urine and kidney stone matrix. The majority of modifiers act as growth inhibitors with varying efficacy.³ Interestingly, we have identified modifiers that function as COM growth promoters.⁴

Understanding the interactions between growth modifiers and crystal interfaces requires a combination of experimental techniques capable of probing a wide range of length and time scales.⁵ Analysis of macroscopic properties (bulk crystal growth) provides information on modifier changes to crystal size and habit. Kinetic studies were employed to assess the effect of modifiers on the rate of COM growth through ion-selective electrochemistry (ISE). To gain molecular insights, it is important to study the interface that captures surface phenomena leading to changes in crystal morphology. For this task, we use in situ atomic force microscopy (AFM) to observe time-resolved dynamics of surface growth in the presence of modifiers.⁶ The culmination of these studies provide insight on how we can potentially engineer modifiers with tailored properties to take advantage of specific modifier-crystal interactions to suppress growth, or even lead to crystal dissolution. To this end, we will present our discovery of modifiers that are viable candidates to replace current therapeutics of pathological COM crystallization.

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2. Farmanesh, S.; Chung, J.; Chandra, D.; Sosa, R. D.; Karande, P.; Rimer, J. D., Journal of Crystal Growth 2013, 373, 13-19.

3. Farmanesh, S.; Alamani, B. G.; Rimer, J. D., Chemical Communications 2015, 51(73), 13964-13967.

4. Farmanesh, S.; Ramamoorthy, S.; Chung, J.; Asplin, J. R.; Karande, P.; Rimer, J. D., Journal of the American Chemical Society 2014, 136(1), 367-376.

5. Rimer, J. D.; An, Z.; Zhu, Z.; Lee, M. H.; Goldfarb, D. S.; Wesson, J. A.; Ward, M. D., Science 2010, 330(6002), 337-341.

6. De Yoreo, J. J.; Chung, S.; Friddle, R. W., Advanced Functional Materials 2013, 23 (20), 2525-2538.