In vitro inhalation cytotoxicity testing of therapeutic nanosystems for pulmonary infection

• Published in: Toxicology in vitro Vol. 63; p. 104714
• Main Authors: Ritter, Detlef, Knebel, Jan, Niehof, Monika, Loinaz, Iraida, Marradi, Marco, Gracia, Raquel, te Welscher, Yvonne, van Nostrum, Cornelus F., Falciani, Chiara, Pini, Alessandro, Strandh, Magnus, Hansen, Tanja
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.03.2020; Elsevier Science Ltd
• Subjects: Air-liquid interface; Alveoli; Antimicrobial peptides; Bioavailability; Biocompatibility; Bronchopulmonary infection; Cytotoxicity; Cytotoxicity testing; Exposure; In vitro; In vitro methods and tests; In vivo methods and tests; Inhalation; Lactose; Liposomes; Lungs; Micelles; Nanoparticles; Nanosystems; Peptides; Pulmonary infection; Respiration; State-of-the-art reviews; Sulfates; Toxicity; Toxicity testing; Toxicology; Toxicity; Antimicrobial peptides; Air-liquid interface; In vitro; Nanosystems; Pulmonary infection; Inhalation
• ISSN: 0887-2333; 1879-3177
• DOI: 10.1016/j.tiv.2019.104714

Due to the increasing need of new treatment options against bacterial lung infections, novel antimicrobial peptides (AMPs) are under development. Local bioavailability and less systemic exposure lead to the inhalation route of administration. Combining AMPs with nanocarriers (NCs) into nanosystems (NSs) might be a technique for improved results. An air-liquid interface (ALI) in vitro inhalation model was set up including a human alveolar lung cell line (A549) and an optimized exposure system (P.R.I.T.® ExpoCube®) to predict acute local lung toxicity. The approach including aerosol controls (cupper-II-sulfate and lactose) delivered lowest observable adverse effect levels (LOAELs). Different combinations of AMPs (AA139, M33) and NCs (polymeric nanoparticles (PNPs), micelles and liposomes) were tested under ALI and submerged in vitro conditions. Depending on the nature of AMP and NCs, packing of AMPs into NSs reduced the AMP-related toxicity. Large differences were found between the LOAELs determined by submerged or ALI testing with the ALI approach indicating higher sensitivity of the ALI model. Since aerosol droplet exposure is in vivo relevant, it is assumed that ALI based results represents the more significant source than submerged testing for in vivo prediction of local acute lung toxicity. In accordance with the current state-of-the-art view, this study shows that ALI in vitro inhalation models are promising tools to further develop in vitro methods in the field of inhalation toxicology. •Nanosystems with antimicrobial peptides for improved drug administration by inhalation.•An in vitro inhalation model to predict acute local lung toxicity was developed.•Packing of antimicrobial peptides into nanosystems could reduce the toxicity.•The extend of toxicity mitigation depended on the nature of peptides and packing.