Enhancement of lung gene delivery after aerosol: a new strategy using non-viral complexes with antibacterial properties

Abstract

The pathophysiology of obstructive pulmonary diseases, such as cystic fibrosis (CF), leads to the development of chronic infections in the respiratory tract. Thus, the symptomatic management of the disease requires, in particular, repetitive antibiotherapy. Besides these antibacterial treatments, certain pathologies, such as CF or chronic obstructive pulmonary disease (COPD), require the intake of many drugs. This simultaneous absorption may lead to undesirable drug interactions. For example, Orkambi® (lumacaftor/Ivacaftor, Vertex), a pharmacological drug employed to treat F508del patients, cannot be used with antibiotics such as rifampicin or rifabutin (rifamycin family) which are necessary to treat Mycobacteriaceae. As far as gene therapy is concerned, bacteria and/or biofilm in the airways present an additional barrier for gene transfer. Thus, aerosol administration of nanoparticles have to overcome many obstacles before allowing cellular penetration of therapeutic compounds. This review focusses on the development of aerosol formulations adapted to the respiratory tract and its multiple barriers. Then, formulations that are currently used in clinical applications are summarized depending on the active molecule delivered. Finally, we focus on new therapeutic approaches to reduce possible drug interactions by transferring the antibacterial activity to the nanocarrier while ensuring the transfection efficiency.

Keywords: Aerosol; Antibacterial properties; Gene delivery; Lung diseases; Nano carriers; multimodal therapy.

Figure 1. The organization and the structure of the respiratory tract

Abbreviation: PCL, periciliary layer.

Figure 2. Pharmacokinetics according to the administration used

The aerosolization allows direct targetting of the lungs and thus bypasses the blood circulation.

Figure 3. Elimination pathways of an inhaled drug

Some of the inhaled drugs are eliminated by exhalation during breathing. The mucociliary clearance leading to the coughing up of sputum allows the more or less rapid elimination of the active ingredients. Once in the trachea, the active ingredients are swallowed and arrive in the digestive tract. Unlike oral administration, few drugs diffuse into the bloodstream due to the small quantity that reaches the pulmonary alveoli, which is the only point of passage to the blood (modified from [35]).

Figure 4. Extracellular factors limiting the therapeutic benefits of an aerosol

Inhaled drugs encounter different physicochemical barriers that can negatively impact their activity. The aerosolization itself is very restrictive for use of drugs. It will determine the size and charge of the aerosolized particles and therefore the deposit site. To interact with eukaryotic cells, particles must penetrate a more or less viscous mucus and limit the interactions with the components and elements trapped in the mucus. ASL contains bacteria, in planktonic form or organized in a biofilm, which can release enzymes capable of degrading the active principle. In addition, bacteria in the form of a biofilm are protected by a very robust exopolyssacharide matrix. Once in contact with eukaryotic cells, the active ingredient must pass through the plasma membrane.

Figure 5. Multifunctional synthetic vectors: an advantage for gene transfer under infectious conditions

The antibacterial activity of a gene transfer system would make it possible to transfect the eukaryotic cells in the presence of bacteria which impair the efficiency of the gene transfer. The production of toxins by bacteria and the induction of an inflammatory response leads to stress or even cell death. The antibacterial effect would eliminate the bacteria on the surface, promoting the transfection process and so the level of expression of the transgene.