Reduced cytotoxicity and enhanced bioactivity of cationic antimicrobial peptides liposomes in cell cultures and 3D epidermis model against HSV
2016 (English)In: Journal of Controlled Release, ISSN 0168-3659, E-ISSN 1873-4995, Vol. 229, 163-171 p.Article in journal (Refereed) PublishedText
Cationic antimicrobial peptides (AMPs) are part of the innate immunity, and act against a wide variety of pathogenic microorganisms by perturbation of the microorganisms plasma membrane. Although attractive for clinical applications, these agents suffer from limited stability and activity in vivo, as well as non-specific interaction with host biological membranes, leading to cytotoxic adverse effects. We hypothesized that encapsulation of AMPs within liposomes could result in reduced cytotoxicity, and with enhanced stability as well as bioactivity against herpes simplex virus 1 (HSV-1). We formulated nano-sized liposomal formulations of LL-37 and indolicidin, and their physicochemical properties, cellular uptake, in vitro cytotoxicity and antiviral efficacy have been determined. Lower cytotoxicity of LL-37 liposomes was found in comparison to indolicidin liposomes attributed to the superior physicochemical properties, and to the different degree of interaction with the liposomal membrane. The disc-like shaped LL-37 liposomes (106.8 +/- 10.1 nm, shelf-life stability of N1 year) were taken up more rapidly and to a significantly higher extent than the free peptide by human keratinocyte cell line (HaCaT), remained intact within the cells, followed by release of the active peptide within the cytoplasm and migration of the vesicles lipids to the plasma membrane. LL-37 liposomes were found significantly less toxic than both the free agent and liposomal indolicidin. In the new 3D epidermis model (immortalized primary keratinocytes) liposomal LL-37 treatment (N20 mu M), but not free LL-37, efficiently protected the epidermis, inhibiting HSV-1 infection. This positive antiviral effect was obtained with no cytotoxicity even at very high concentrations (400 mu M). Thus, the antiviral activity of encapsulated LL-37 was significantly improved, expanding its therapeutic window. Liposomal LL-37 appears to be a promising delivery system for HSV therapy. (C) 2016 Elsevier B.V. All rights reserved.
Place, publisher, year, edition, pages
ELSEVIER SCIENCE BV , 2016. Vol. 229, 163-171 p.
Drug delivery system; Liposomes; Antimicrobial peptides; LL-37; Indolicidin; Peptide delivery; Disc-like liposomes; HSV-1; 3D epidermis model
Physical Sciences Clinical Medicine
IdentifiersURN: urn:nbn:se:liu:diva-128724DOI: 10.1016/j.jconrel.2016.03.025ISI: 000375218900015PubMedID: 27012977OAI: oai:DiVA.org:liu-128724DiVA: diva2:932353
Funding Agencies|Fraunhofer Institute (Germany) - Hebrew University of Jerusalem (Israel); Sir Zelman Cowen Universities Fund2016-06-012016-05-302016-06-01