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Surface interactions between oligopeptide derivatives of salicylic acid and calcite as a model of an inorganic drug delivery system

Targeted or sustained drug delivery is a promising strategy for improving the therapeutic efficiency of existing active pharmaceutical molecules. Typically, liposomal, micellar or biodegradable polymeric matrices are used for encapsulation of model drug molecules and/or design of new drug delivery systems. Recently, however, porous inorganic materials have been proposed as suitable carriers. Calcium carbonate is a rather common mineral, which has been considered as a mineral drug carrier due to recognized biocompatibility, nontoxicity and biodegradability. Indeed, it has been suggested that CaCO3 may significantly improve drug stability and bioavailability, as well as to control the release of active compounds by influencing their desorption and/or dissolution rates. However, the understanding of the basic molecular interactions of model pharmaceutical compounds with mineral surfaces is a critical step in the development of efficient CaCO3 based hybrid materials that could be used as biocompatible carriers in drug delivery systems. Previously, we studied the molecular interactions between well defined calcite surfaces and salicylic acid (Sal), as well as its derivatives, which were selected as a simple models of anti-inflammatory drug substances. The inspiration for derivatization of salicylic acid molecules with glutamic acid (Glu) or aspartic acid (Asp) is taken from the process of biomineralization, in which organic- inorganic hybrid materials are composed of CaCO3 polymorphs (calcite or aragonite) and Asp-rich acidic glycoproteins. The synthesized amino acid adducts with Sal exerted significantly enhanced binding to specific calcite surfaces, in comparison to free Sal. The aim of this study is to design new salicylic acid adducts, which should be biocompatible and water-soluble. The adducts should also enable stronger Sal binding by means of multiple carboxylic groups, while the linkers should be easily cleaved after binding to CaCO3 surface. Thus, we designed and synthesized 6 tripeptides (L-Asp-L-Asp-L-Asp ; D-Asp-D-Asp-D-Asp ; L-Asp-D-Asp-L-Asp ; L-Asp- Gly-L-Asp ; L-Asp--Ala-L-Asp and L-Asp-Gly-D- Asp), as well as the respective adducts with salicylic acid (Sal-Gly-L-Asp-D-Asp-L-Asp ; Sal- L-Asp-D-Asp-L-Asp ; Sal-Gly-L-Asp-L-Asp-L-Asp and Sal-L-Asp-L-Asp-L-Asp) in order to test the efficiency of their binding with rhombohedral calcite crystals bounded by the stable {; ; 1 0 4}; ; faces. The efficiency has been correlated with the number of carboxylic groups, their orientation in space, charge separation effect and chirality of α-carbon atom. The qualitative compliance of the results of molecular dynamics calculations (MD) of binding energies (Eb = -755 kJ mol-1) and the Langmuir adsorption constants (Kad = 0.56 dm3 mol-1), determined from the crystal growth kinetics of calcite crystals in the presence of respective adducts, indicated the strongest interactions of L-Asp- D-Asp-L-Asp. Similarly, the MD and the crystal growth kinetic data showed the strongest surface interactions of Sal-Gly-L-Asp-D-Asp-L- Asp (Kad = 1.58 dm3 mol-1). The obtained results and proposed systematic approach (MD and crystal growth kinetics) can contribute to a better understanding of molecular interactions between model drug derivatives containing carboxylic functional groups with mineral surfaces, thus being the basis for the design of efficient mineral drug delivery systems.

calcite, salicylic acid, drug delivery

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