Diabetes mellitus affects about 12.6% of the population in the United States. Neuropathy due to high sugar levels is a common cause of chronic foot ulcers in diabetic patients. The ulcers do not heal quickly due to underlying pathologies and therefore, become a breeding ground for bacteria. These infections are difficult-to-treat with conventional antibiotics because the bacteria form a layer of matrix around them called biofilm. Management costs of these infections run in billions of dollars, and significantly deteriorates the quality of life of the affected individuals. To treat these infections, development of a liposomal drug delivery system that can penetrate the bacterial biofilms, not get cleared by human immune cells immediately, and thereby effectively deliver the antibiotics would be ideal. Here we demonstrate the proof-of-concept for one such liposomal drug delivery system that contains a zwitterionic polymer called poly-(carboxybetaine) (PCB) conjugated to a phospholipid, and encapsulates antimicrobial agents. Unlike the current industry standard poly-(ethylene glycol) (PEG), use of PCB does not require cholesterol in the lipid bilayer to stabilize the liposomes. Synthesis of PCB polymer was carried out using reversible addition-fragmentation chain transfer (RAFT) polymerization and degree of polymerization was verified through proton nuclear magnetic resonance (1H-NMR). Subsequently, the PCB polymer was conjugated to 1,2-distrearoyl-sn-glycero-3-phosphoethanolamine (DSPE) and liposomes were synthesized using microfluidics. Liposome characterization was performed for size, charge, encapsulation efficiency and drug release profile. To evaluate the efficacy of the drug delivery system, liposomal penetration into the bacterial biofilms, and ability of the drug-loaded liposomes in eradicating pre-formed biofilms was determined. The data suggests that the liposomes can penetrate the bacterial biofilms of both Gram-positive and Gram-negative bacteria in a time-dependent manner. The drug-loaded liposomes can completely inhibit biofilm formation and result in upto 60% reduction of bacterial viability in the Pseudomonas aeruginosa (PA) biofilms, even with the usage of significantly lower antibiotic concentration as compared to the free drug. Future work would involve studying the rate of phagocytosis of these liposomes by M1 macrophages (in vitro) that are predominantly found in the wound environment and subsequently in an in vivo diabetic wound model.

Liposomal drug delivery for wound infections in diabetic foot ulcers

ACS Spring 2022

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