Optimizing the Crystallization and Coating of Drugs for Regenerative Medicine

Regenerative medicine is an emerging field that uses engineered biomaterials in tandem with the human body’s natural healing process to regenerate damaged tissue and organs. Recent studies on Murphy Roths Large (MRL) mice demonstrated their capability to regenerate injured tissue due to an overexpression of hypoxia-inducible factor-1α (HIF-1α) throughout the initial stages of the wound healing process. A therapeutic strategy to beneficial upregulation of HIF-1α is through inhibition of prolyl hydroxylase (PHD), an enzyme that regulates HIF-1α levels through hydroxylation of proline residues, leading to degradation of HIF-1α. Recently we reported the use of a small molecule drug inhibitor of PHD for tissue regeneration. Since this class of drugs are poorly soluble, development of new formulations may open the door to further enhancements in regenerative medicine. The objective of this study is to enhance the efficacy of a PHD inhibitor through crystal surface engineering. In particular, we are interested in surface modifications that increase the solubility of insoluble drugs. One approach is to incorporate mussel-inspired polymers, like polydopamine (pDA) coating on nanoparticles, to improve drug targeting, residence time and bioavailability. Therefore, in this study, the drug release and encapsulation efficiency of pDA-coated PHD inhibitor nanocrystals were thoroughly investigated. Drug crystal fabrication was performed using flash nanoprecipitation, where the modification of preparation conditions were employed to control crystal size. For example, by changing the aqueous to organic ratio of crystallization solvent, mixing and cooling temperatures, crystal size decreased by 93%. Additional optimization of the pDA coating was performed. The pDA-coated drug crystals were analyzed by TEM and drug release studies were conducted with HPLC. This innovative approach leverages both potential pro-regenerative drugs with bio-inspired coatings to facilitate the development of next-generation drug targeting and tissue regeneration.