Evaluating β 2 -agonists as siRNA delivery adjuvants for pulmonary surfactant-coated nanogel inhalation therapy.

Autor: Merckx P; Ghent Research Group on Nanomedicines, Laboratory of General Biochemistry and Physical Pharmacy, Faculty of Pharmaceutical Sciences, Department of Pharmaceutics, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium. Electronic address: pieterjan.merckx@ugent.be., Conickx G; Laboratory for Translational Research in Obstructive Pulmonary Diseases, Faculty of Medicine and Health Sciences, Department of Respiratory Medicine, Ghent University Hospital, Medical Research Building 2, Corneel Heymanslaan 10, 9000 Ghent, Belgium. Electronic address: griet.conickx@ugent.be., Blomme E; Laboratory for Translational Research in Obstructive Pulmonary Diseases, Faculty of Medicine and Health Sciences, Department of Respiratory Medicine, Ghent University Hospital, Medical Research Building 2, Corneel Heymanslaan 10, 9000 Ghent, Belgium. Electronic address: evy.blomme@ugent.be., Maes T; Laboratory for Translational Research in Obstructive Pulmonary Diseases, Faculty of Medicine and Health Sciences, Department of Respiratory Medicine, Ghent University Hospital, Medical Research Building 2, Corneel Heymanslaan 10, 9000 Ghent, Belgium. Electronic address: tania.maes@ugent.be., Bracke KR; Laboratory for Translational Research in Obstructive Pulmonary Diseases, Faculty of Medicine and Health Sciences, Department of Respiratory Medicine, Ghent University Hospital, Medical Research Building 2, Corneel Heymanslaan 10, 9000 Ghent, Belgium. Electronic address: ken.bracke@ugent.be., Brusselle G; Laboratory for Translational Research in Obstructive Pulmonary Diseases, Faculty of Medicine and Health Sciences, Department of Respiratory Medicine, Ghent University Hospital, Medical Research Building 2, Corneel Heymanslaan 10, 9000 Ghent, Belgium. Electronic address: guy.brusselle@ugent.be., De Smedt SC; Ghent Research Group on Nanomedicines, Laboratory of General Biochemistry and Physical Pharmacy, Faculty of Pharmaceutical Sciences, Department of Pharmaceutics, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium. Electronic address: stefaan.desmedt@ugent.be., Raemdonck K; Ghent Research Group on Nanomedicines, Laboratory of General Biochemistry and Physical Pharmacy, Faculty of Pharmaceutical Sciences, Department of Pharmaceutics, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium. Electronic address: koen.raemdonck@ugent.be.
Jazyk: angličtina
Zdroj: European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V [Eur J Pharm Biopharm] 2024 Apr; Vol. 197, pp. 114223. Date of Electronic Publication: 2024 Feb 15.
DOI: 10.1016/j.ejpb.2024.114223
Abstrakt: The lung is an attractive target organ for inhalation of RNA therapeutics, such as small interfering RNA (siRNA). However, clinical translation of siRNA drugs for application in the lung is hampered by many extra- and intracellular barriers. We previously developed hybrid nanoparticles consisting of an siRNA-loaded nanosized hydrogel (nanogel) core coated with Curosurf®, a clinically used pulmonary surfactant. The surfactant shell was shown to markedly improve particle stability and promote intracellular siRNA delivery, both in vitro and in vivo. However, the full potential of siRNA nanocarriers is typically not reached as they are rapidly trafficked towards lysosomes for degradation and only a fraction of the internalized siRNA cargo is able to escape into the cytosol. We recently reported on the repurposing of widely applied cationic amphiphilic drugs (CADs) as siRNA delivery enhancers. Due to their physicochemical properties, CADs passively accumulate in the (endo)lysosomal compartment causing a transient permeabilization of the lysosomal membrane, which facilitates cytosolic drug delivery. In this work, we assessed a selection of cationic amphiphilic β 2 -agonists (i.e., salbutamol, formoterol, salmeterol and indacaterol) for their ability to enhance siRNA delivery in a lung epithelial and macrophage cell line. These drugs are widely used in the clinic for their bronchodilating effect in obstructive lung disease. As opposed to the least hydrophobic drugs salbutamol and formoterol, the more hydrophobic long-acting β 2 -agonist (LABA) salmeterol promoted siRNA delivery in both cell types for both uncoated and surfactant-coated nanogels, whereas indacaterol showed this effect solely in lung epithelial cells. Our results demonstrate the potential of both salmeterol and indacaterol to be repurposed as adjuvants for nanocarrier-mediated siRNA delivery to the lung, which could provide opportunities for drug combination therapy.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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