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Title: Light-responsive delivery and photothermal enhancement of antimicrobial peptides to combat bacterial wound infections
Author: Moorcroft, Samuel Charles Tensin
ISNI:       0000 0004 9357 8417
Awarding Body: University of Leeds
Current Institution: University of Leeds
Date of Award: 2020
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Antibiotic overuse has driven the development of antimicrobial resistance (AMR), whilst a dwindling antibiotic development pipeline has led to the emergence of resistance to "last resort" antibiotics, such as carbapenem. Antimicrobial peptides (AMPs) are emerging as a promising means of treating multidrug resistant bacterial infections, with reduced risk of AMR development due to the AMP efficacy and rapid bactericidal effects. Clinical translation of AMPs is hindered by peptide susceptibility to proteolytic degradation, low biostability and unknown potential for systemic toxicity. Stimuli-responsive AMP delivery systems offer a promising means of circumventing these shortcomings with spatial and temporal control over drug delivery increasing drug pharmacodynamics, thus permitting the use of lower drug doses. Furthermore, the encapsulation of an AMPs inside a delivery vehicle can improve biostability and protect the cargo from proteolytic degradation. This thesis discusses the development of a prototype poly(ethylene glycol) (PEG) hydrogel wound dressing that contains phospholipid coated gold nanorods (AuNRs) and liposomes loaded with the AMP IRIKIRIK-CONH2 (IK8). Using facile lipid film hydration techniques, liposomes were fabricated to encapsulate lethal doses of IK8 and protect the internalised peptides from protease degradation. The liposomes exhibit negligible leakage until heated to the gel-fluid phase transition temperature in the presence of bacteria. The bulk temperature of the gel can be controlled by varying the intensity of applied continuous wave irradiation that mediates the AuNR photothermal heating profile. Irradiation at 2.1 W cm-2 for 10 mins (heating the sample to 55°C demonstrated triggered delivery of IK8, eliciting bactericidal activity against Staphylococcus aureus and Pseudonomas aeruginosa. Irradiation at 2.4 W cm-2 (heating the sample to 60°C for 10 mins) demonstrated thermal bacteria killing alone, and an additive antibacterial effect in conjunction with the AMP. Through controlling μthe concentration of IK8-liposomes and the laser irradiation time a single gel can provide bactericidal activity against multiple batches of bacteria. Additionally, by mixing maleimide-functionalised phospholipid stabilised AuNRs with IK8-loaded liposomes containing the thiolated lipid DPPE-Ptd, AuNR conjugated IK8-liposome (ANCIL) complexes were fabricated that enabled the triggered release of AMPs under pulsed laser irradiation (450 μJ cm-2 for 10 mins) without bulk heating. The ANCIL complexes demonstrate a >3-log reduction in viable S. aureus compared to non-irradiated equivalents.
Supervisor: Evans, Stephen D. ; Ong, Zhan Yuin ; Jayne, David G. Sponsor: EPSRC
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available