Journal Article

Inflammation-targeted delivery of Urolithin A mitigates chemical- and immune checkpoint inhibitor-induced colitis

Dryden, Gerald W., Ghosh, Sweta, Sunnapu, Omprakash, Li, Hong, Vemula, Praveen Kumar, Haribabu, Bodduluri, Singh, Rajbir, Nukavarapu, Syam P., Jala, Venkatakrishna Rao, Goap, Tanu Jain, Vanwinkle, Zachary M.

2024

Overview

Inflammatory bowel disease (IBD) treatment often involves systemic administration of anti-inflammatory drugs or biologics such as anti-TNF-α antibodies. However, current drug therapies suffer from limited efficacy due to unresponsiveness and adverse side effects. To address these challenges, we developed inflammation-targeting nanoparticles (ITNPs) using biopolymers derived from the gum kondagogu ( Cochlospermum gossypium ) plant. These ITNPs enable selective drug delivery to inflamed regions, offering improved therapeutic outcomes. We designed ITNPs that specifically bind to inflamed regions in both human and mouse intestines, facilitating more effective, uniform, and prolonged drug delivery within the inflamed tissues. Furthermore, we demonstrated that oral administration of ITNPs loaded with urolithin A (UroA), a microbial metabolite or its synthetic analogue UAS03 significantly attenuated chemical- and immune checkpoint inhibitor- induced colitis in pre-clinical models. In conclusion, ITNPs show great promise for delivering UroA or its analogues while enhancing therapeutic efficacy at lower doses and reduced frequency compared to free drug administration. This targeted approach offers a potential solution to enhance IBD treatment while minimizing systemic side effects. Significance Inflammatory Bowel Disease (IBD) is a complex medical condition characterized by alternating phases of inflammation and remission in the gastrointestinal tract. Despite the success of immune checkpoint inhibitors (ICI) in cancer therapy, ICI-mediated colitis remains a challenge for cancer patients. Current treatments targeting systemic inflammation have limitations and adverse effects. To overcome these challenges, we have developed inflammation-targeted nanoparticles from natural compounds to deliver the microbial metabolite urolithin A or its synthetic analog UAS03 to inflammatory sites to ameliorate colitis. Our data showed that oral treatment with these nanoparticles attenuated chemically induced and ICI-triggered colitis in preclinical models. These studies highlight the utilization of these inflammation-targeted nanoparticles to deliver urolithin A will have significant implications for the treatment of IBD.

• Publisher: BioMed Central,BMC
• Subject: Advanced 2D nanomaterials for biomedical applications / Animals / Anti-Inflammatory Agents - chemistry / Anti-Inflammatory Agents - pharmacology / Anti-Inflammatory Agents - therapeutic use / Biotechnology / Chemistry / Chemistry and Materials Science / Colitis - chemically induced / Colitis - drug therapy / Coumarins - chemistry / Coumarins - pharmacology / Disease Models, Animal / Drug Delivery Systems - methods / Female / Humans / Immune check point inhibitor-induced colitis / Immune Checkpoint Inhibitors - pharmacology / Inflammation - drug therapy / Inflammation-targeting nanoparticles / Inflammatory bowel diseases / Inflammatory Bowel Diseases - drug therapy / Mice / Mice, Inbred C57BL / Microbial metabolite / Molecular Medicine / Nanoparticles - chemistry / Nanotechnology / Urolithin A