(265d) Biodegradable Bile Salt Particles for Local Fat Reduction: Tuning Particles' Self-Assembly for Improved Drug Delivery

Bile acids, which are naturally occurring molecules have gained wide attention due to their surfactant properties. For instance, FDA-approved Deoxycholic acid (Kybella) is used for the local reduction of fat; ursodeoxycholic acid is used for reducing gallbladder stones. However, since bile acids are administered in the solubilized form, multiple drug dosage is required to maintain the therapeutic amount of this drug in the body. This multiple dosage results in inflammation and ulceration in the case of deoxycholic acid, hence limiting its clinical application. Recently, bile salt particles have been developed an as alternative to bile acid/salt solutions. However, their large sizes make them unattractive for intravenous delivery to achieve a systemic therapeutic effect.

Therefore, this work focuses on elucidating the mechanism of particle self-assembly to give control over their shapes and sizes. In this study, we demonstrated the ability to tune bile salt particles’ shapes and sizes by modifying either the steroid core or the side chain of bile acids. The results of this work show that bile salt particles will only be formed when the side group is ionizable at the fabricating pH. Provided the side group undergoes ionization, we found that the size of the particles formed is dependent on the flexibility of the side group, which is analogous to its chain length (number of carbon atoms) for an aliphatic group. We also demonstrate that the self-assembly of particles into different shapes is affected by the number, position and/or stereochemistry of the hydroxyl groups attached to the steroid core of bile acids, confirming previous computational studies. This is an important discovery because particles’ shape and size play a key role in their bioavailability in the body.

Furthermore, the focus of this work was on bile acids conjugated to amino acid, suggesting that the resulting biodegradable bile salt particles are biocompatible. This is because the conjugation of amino acids (glycine and taurine) to bile acids occurs naturally in the liver. Also, there is evidence that elongated particles do not readily experience phagocytosis by macrophages, hence we do not foresee challenges with the local delivery of our bile salt particles.

Since we successfully demonstrated the ability to synthesize a wide range of amino acid-modified bile acids, we will explore other modifications to the steroid core and/or side group in the future. These modifications will be aimed at reducing the particle sizes to the submicron scale to make them attractive for intravenous delivery, to achieve a systemic therapeutic effect. Furthermore, we are interested in conducting similar studies on corticosteroids, another important member of the steroid family. Having similar chemical structures as bile acids, corticosteroids are anti-inflammatory agents widely used in the treatment of arthritis, covid-19, among others.

In summary, the ability to form bile salt particles with varying shapes and sizes by making slight modification to the chemical structure of bile acids as shown in this work presents opportunities for clinical translations. Furthermore, these particles were also seen to retain their bioactivity in inducing fat cell-death. Hence, having control over the shape and size of bile salt particles while retaining their efficacy will open doors for clinical translations.