Use of traditional antibiotics presents problems of selection and survival of resistant pathogens because of the direct killing mechanism including inhibition of bacterial cell wall synthesis and interference of protein synthesis. Hence, new approaches for treatment of surgical site infection (SSI) or contaminated wounds with a mode of action different from current anti-infectives are imperatively needed and useful in addressing multiple antibiotic resistant organisms. Human cathelicidin LL-37 is a small cationic peptide that can act as an antibiotic by disrupting the membrane of microbes. LL-37 is derived from an inactive proform (hCAP-18) produced in humans by various types of cells following exposure to active vitamin D (1,25-hydroxyvitamin D3 – 1,25(OH)2D) with local production critically dependent on the storage form of vitamin D – 25-hydroxyvitamin D3 – 25(OH)D. Direct LL- 37 peptide application and over expression following gene therapy approaches have been used to alter local concentrations of LL-37 but significant issues have developed precluding this direct approach: toxicity to eukaryotic cells, formation of toroidal pore, and risk of unintended and undesired tissue destruction and inflammation in the area of surgical incisions and traumatic wounds. In addition, parathyroid hormone-related peptide (PTHrP) was recently demonstrated to significantly enhance the production of LL-37 when co-administrated with 25(OH)D. This study proposes a novel approach by making use of electrospun nanofibers as drug carriers for the delivery of 25(OH)D and PTHrP to the surgical site topically and induce innate immune response to produce antimicrobial peptides and thus prevent SSIs, which can shorten the average length of hospital stay. Since the critical substrates 25(OH)D and PTHrP are being delivered in this novel approach, the normal host machinery for antimicrobial peptide production is optimized eliminating the risks associated with direct peptide delivery. Our objective is that these nanofiber-based wound dressings will be used in the clinical settings for successful prevention of SSIs either as coatings to implants, barrier dressings or wound closure strategies. The strategy will also provide a significant benefit in the near term to individuals who have wounds, trauma, and orthopaedic injuries and has a significant impact on unit readiness.

Local sustained co-delivery of 25-hydroxyvitamin D3 and parathyroid hormone-related peptide for overcoming antimicrobial resistance

249th National Meeting (2015)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.