Safety and effectiveness of sodium-colistimethate-loaded nanostructured lipid carriers (SCM-NLC) against P. aeruginosa: in vitro and in vivo studies following pulmonary and intramuscular administration
- Vairo1,2, J. Basas3, M. Pastor1, G. Gainza1, M. Moreno-Sastre2,4, X. Gomis3, A. Fleischer5,6, E. Palomino5,6, D. Bachiller5,6, F.B. Gutiérrez7, J.J. Aguirre1,7, A. Esquisabel2,4, M. Igartua2,4, E. Gainza1, R.M. Hernandez2,4, J. Gavaldà3 & J.L. Pedraz2,4
1BioPraxis Research AIE, R&D Department, Hermanos Lumière, 5, 01510 Miñano (Araba), Spain
2NanoBioCel Group, Laboratory of Pharmaceutics, University of the Basque Country, School of Pharmacy, Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain
3Antimicrobial Resistance Laboratory, Vall d’Hebron Research Institute (VHIR). Infectious Diseases Department, Hospital Universitari Vall d’Hebron, Passeig de la Vall d’Hebron, 119-129, 08035 Barcelona
4Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN). Vitoria-Gasteiz, Spain
5Fundación Investigaciones Sanitarias Islas Baleares (FISIB), Development and Regeneration Program, Ctra. Sóller km 12, 07110 Bunyola (Balearic Islands), Spain
6Consejo Superior de Investigaciones Científicas (CSIC), Ctra. Sóller km 12, 07110 Bunyola (Balearic Islands), Spain
7Department of Pathological Anatomy, Hospital Universitario de Álava (HUA). José Atxotegi, 01009 Vitoria-Gasteiz, Spain
In an effort to make a step forward optimising the administration of antibiotics mainly improving their effectiveness and safety, in the present study we have developed a novel formulation against different Pseudomans aeruginosa (Pa) multiresistant clinical isolates based on sodium colistimethate-loaded nanostructured lipid carriers (SCM-NLC), administered by the pulmonary and intramuscular routes. In the present study the effectiveness, safety and biodistribution of SCM-NLC have been tested against non-encapsulated SCM, using both in vitro and in vivo models.
The aims of this study were the follows; first, to prepare SCM-NLC and prove their in vitro antimicrobial activity against different multiresistant P. aeruginosa (MR-Pa) clinical isolates; second, to evaluate the toxicity, the biodistribution and the effectiveness of the pulmonary administration of nebulised SCM-NLC and intramuscular (IM) administration of SCM-NLC against an extensively drug-resistant (XDR)-Pa strain in an acute pneumonia model in mice.
With this interdisciplinary research, we found that (i) encapsulation process enhances the pharmacological efficacy compared to free SCM in vivo; (ii) nanoencapsulation resulted in reduced toxicity, especially nephrotoxicity; (iii) the pulmonary administration resulted in low systemic absorption while the intramuscular administration showed greater systemic absorption. Thus, the pulmonary route might be selected in case of maintenance therapy for its effect in lungs, whereas, intramuscular route may be more useful in an emergency as it showed a faster absorption.
In conclusion, the results showed herein may represent an important demonstration of the therapeutic potential of SCM-NLC against P. aeruginosa in vivo.