Encapsulation of SAAP-148 in Octenyl Succinic Anhydride-Modified Hyaluronic Acid Nanogels for Treatment of Skin Wound Infections

Abstract

Chronic wound infections colonized by bacteria are becoming more difficult to treat with current antibiotics due to the development of antimicrobial resistance (AMR) as well as biofilm and persister cell formation. Synthetic antibacterial and antibiofilm peptide (SAAP)-148 is an excellent alternative for treatment of such infections but suffers from limitations related to its cationic peptidic nature and thus instability and possible cytotoxicity, resulting in a narrow therapeutic window. Here, we evaluated SAAP-148 encapsulation in nanogels composed of octenyl succinic anhydride (OSA)-modified hyaluronic acid (HA) to circumvent these limitations. SAAP-148 was efficiently (>98%) encapsulated with high drug loading (23%), resulting in monodispersed anionic OSA-HA nanogels with sizes ranging 204–253 nm. Nanogel lyophilization in presence of polyvinyl alcohol maintained their sizes and morphology. SAAP-148 was sustainedly released from lyophilized nanogels (37–41% in 72 h) upon reconstitution. Lyophilized SAAP-148-loaded nanogels showed similar antimicrobial activity as SAAP-148 against planktonic and biofilm-residing AMR Staphylococcus aureus and Acinetobacter baumannii. Importantly, formulated SAAP-148 showed reduced cytotoxicity against human erythrocytes, primary human skin fibroblasts and human keratinocytes. Additionally, lyophilized SAAP-148-loaded nanogels eradicated AMR S. aureus and A. baumannii colonizing a 3D human epidermal model, without inducing any cytotoxicity in contrast to SAAP-148. These findings indicate that OSA-HA nanogels increase SAAP-148′s therapeutic potential for treatment of skin wound infections.

Nanogel-based composites for bacterial antibiofilm activity: advances, challenges, and prospects

“…HA-based nanogels have also been investigated as carriers for several other AMPs such as the synthetic antimicrobial and antibiofilm peptide (SAAP)-148 (ref. 7 and 65), the snake cathelicidin Ab-Cath, 7,8 and DJK-5. 62 Peptides with antimicrobial and antibiofilm activities are promising alternatives to antibiotics for the treatment of AMR bacterial infections.…”

“…The encapsulation within the nanogel also prevented the typical unwanted SAAP-associated toxicity. 65 While the nanogels demonstrated impressive results in in vitro models, the proteolytic stability of SAAP-148 post-encapsulation in HA nanogels still needs to be examined with proteases. A more comprehensive evaluation using in vivo models could provide a deeper understanding of the pharmacokinetic and pharmacodynamic properties of the drug delivery system.…”

“…Furthermore, creating a larger scale delivery system, like a gel, cream, or ointment, that contains the SAAP-148-loaded OSA-HA nanogels could aid in evaluating the potential of this nanoscale delivery system for clinical use as an antimicrobial treatment. 65 Another study by Van Gent et al 7 encapsulated both Ab-Cath and SAAP-148 within HA-based nanogels and assessed their antimicrobial activity against AMR S. aureus and A. baumannii . Although this study showed reduced peptide-associated toxicity and maintained peptide-associated antimicrobial activity in AMR S. aureus and A. baumannii , this study did evaluate the performance of the loaded nanogels on the AMR strains residing within biofilms.…”