Oral liposomal delivery of an activatable budesonide prodrug reduces colitis in experimental mice

Abstract

Inflammatory bowel disease (IBD) is one of the most common intestinal disorders, with increasing global incidence and prevalence. Numerous therapeutic drugs are available but require intravenous administration and are associated with high toxicity and insufficient patient compliance. Here, an oral liposome that entraps the activatable corticosteroid anti-inflammatory budesonide was developed for efficacious and safe IBD therapy. The prodrug was produced via the ligation of budesonide with linoleic acid linked by a hydrolytic ester bond, which was further constrained into lipid constituents to form colloidal stable nanoliposomes (termed budsomes). Chemical modification with linoleic acid augmented the compatibility and miscibility of the resulting prodrug in lipid bilayers to provide protection from the harsh environment of the gastrointestinal tract, while liposomal nanoformulation enables preferential accumulation to inflamed vasculature. Hence, when delivered orally, budsomes exhibited high stability with low drug release in the stomach in the presence of ultra-acidic pH but released active budesonide after accumulation in inflamed intestinal tissues. Notably, oral administration of budsomes demonstrated favorable anti-colitis effect with only ∼7% mouse body weight loss, whereas at least ∼16% weight loss was observed in other treatment groups. Overall, budsomes exhibited higher therapeutic efficiency than free budesonide treatment and potently induced remission of acute colitis without any adverse side effects. These data suggest a new and reliable approach for improving the efficacy of budesonide. Our in vivo preclinical data demonstrate the safety and increased efficacy of the budsome platform for IBD treatment, further supporting clinical evaluation of this orally efficacious budesonide therapeutic.

Keywords:

• Budesonide
• prodrug
• liposome
• activatable
• inflammatory bowel disease

Acknowledgments

We thank Wu Lingyun in the Center of Cryo-Electron Microscopy (CCEM), Zhejiang University for her technical assistance on Cryo-EM Scanning Electron Microscopy.

Data availability statement

The data are available from the corresponding author ([email protected]) on reasonable request.

Disclosure statement

The authors declare no potential conflicts of interest.

Ethical approval statement

ll animal studies were conducted in accordance with the National Institute Guide for the Care and Use of Laboratory Animals. Experimental protocols were approved by the Animal Ethics Committee of the First Affiliated Hospital, Zhejiang University School of Medicine.

Additional information

Funding

This work was supported by Zhejiang Provincial Natural Science Foundation of China (LR19H160002), National Natural Science Foundation of China (82273490, 82073296, and 81773193), Research Project of Jinan Microecological Biomedicine Shandong Laboratory (JNL-2022010B), Clinical Research Project of Shanghai Municipal Health Commission (202140100), Minsheng Research Project of Pudong New Area Science and Technology Development Fund (PKJ2022-Y39), and Medical Discipline Construction Project of Pudong Health Committee of Shanghai (PWYts2021-18).