(489d) A Computational Approach to Predicting the Self-Assembly of Particle-Based Steroid Therapeutics

Since their clinical introduction over 70 years ago, steroid-core drugs have been used in several areas of medicine. For example, corticosteroids, such as dexamethasone and prednisolone, are used in the treatment of Covid-19, arthritis, and many other inflammatory conditions. Also belonging to the same steroid-core family of drugs as corticosteroids, bile acids, such as cholic acid and deoxycholic acid, are widely administered to patients with, but not limited to, gall stones, liver diseases, and excessive submental fat.

However, current formulations of these solubilized steroid-core therapeutics suffer from a high clearance rate upon administration, resulting in low bioavailability. Unfortunately, multiple dosing or higher doses lead to local or off-target side effects, for example, ulceration and suppression of the immune system, respectively and noncompliance of patients.

To combat the current challenges of steroid-core therapeutics, particle-based formulations of some bile acids – specifically cholate, deoxycholate, ursodeoxycholate, lithocholate, and chenodeoxycholate – and corticosteroids, namely, methylprednisolone, hydrocortisone, and dexamethasone, was developed using the double solvent emulsion evaporation (DSEE) technique. In this work, the tunability of steroid particles’ sizes was demonstrated, which is an important parameter in the administration of particle-based drug delivery systems. Particle tunability was also confirmed with a preliminary coarse-grained computational simulation of particle self-assembly, which somewhat agreed with the experimental results. It was also discovered that despite the modification of deoxycholate particles’ sizes, their bioactivity and biodegradability were not negatively impacted.

This study further sought to accurately elucidate the self-assembly mechanism of steroid-core particles and build a library of clinically relevant steroid-core drugs. The systematic coarse-grained model used in this work captures the individual molecular contributions of the steroids’ core (base structure) and the extendable tail. Furthermore, the resulting molecular packing of steroid monomers shown in this work agrees with the experimental result to a higher degree than that previously reported. Similarly, this improved systematic coarse-grained modeling was extended to predict the particles’ shapes and sizes for other steroid-core drugs if fabricated with the DSEE technique. The library of steroid-core drugs built comprises of Spironolactone, proposed for the treatment of heart diseases, Formestane (Breast cancer), Trodusquemine (Diabetes), Prednimustine (Leukemia), Abiraterone (Prostate cancer), Onapristone (Breast cancer), Aramchol (Fatty liver disease) and Caprospinol (Alzheimer’s disease).

Without a doubt, our ability to accurately predict the self-assembly of steroid-core molecules with the coarse-grained computational model offers a cost-effective method of obtaining steroid-based drug particles in real-time. Also, we have previously shown that the sizes of particles fabricated with deoxycholate, a steroid-core molecule, can be altered by modifying its side chain. Therefore, our robust computational model can potentially be useful for determining the suitable side group modification necessary to achieve the desired particles’ size, depending on the clinical application. Thus, this study opens opportunities for clinically combating numerous conditions using particle-based steroid therapeutics.