Lipidic Prodrug Co-Crystals: A Platform for Combination Therapy Targeting Fungal Biofilms

Area of Science:

• Pharmaceutical Science
• Drug Delivery Systems
• Mycology

Background:

• Fungal infections are often complicated by biofilms and inflammation, reducing conventional antifungal therapy effectiveness.
• Developing advanced drug delivery systems is crucial to overcome these therapeutic challenges.

Purpose of the Study:

• To develop and evaluate a novel hybrid drug delivery platform, lipidic prodrug co-crystals (LPCCs), for treating fungal infections.
• To investigate the efficacy of LPCCs in preventing and eradicating fungal biofilms and mitigating inflammation.

Main Methods:

• Synthesized a lipidic prodrug by linking α-aminophosphonate with phenylboronic acid-modified bifonazole (Bfz).
• Co-crystallized the lipidic prodrug with nonsteroidal anti-inflammatory drugs (NSAIDs) to form LPCCs.
• Evaluated LPCCs' drug-loading capacity, controlled release, biofilm inhibition, and anti-inflammatory effects in vitro and in a murine rectal candidiasis model.

Main Results:

• LPCCs demonstrated high drug-loading capacity (up to 85%) and co-crystallized effectively with NSAIDs.
• The dual-delivery system provided controlled, site-specific release of antifungal and anti-inflammatory agents in response to the biofilm microenvironment.
• LPCCs significantly prevented biofilm formation, eradicated mature biofilms, reduced inflammation by inhibiting the NF-κB/COX-2 pathway, and improved outcomes in a murine candidiasis model.

Conclusions:

• Lipidic prodrug co-crystals (LPCCs) represent a promising hybrid drug delivery platform for fungal infections.
• LPCCs enhance antifungal efficacy, reduce inflammation, and offer a potential strategy to overcome limitations of current therapies.