Carriers for the targeted delivery of aerosolized macromolecules for pulmonary pathologies

Abstract

Introduction: Macromolecules with unique effects and potency are increasingly being considered for application in lung pathologies. Numerous delivery strategies for these macromolecules through the lung have been investigated to improve the targeting and overall efficacy.Areas covered: Targeting approaches from delivery devices, formulation strategies and specific targets are discussed.Expert opinion: Although macromolecules are a heterogeneous group of molecules, a number of strategies have been investigated at the macro, micro, and nanoscopic scale for the delivery of macromolecules to specific sites and cells of lung tissues. Targeted approaches are already in use at the macroscopic scale through inhalation devices and formulations, but targeting strategies at the micro and nanoscopic scale are still in the laboratory stage. The combination of controlling lung deposition and targeting after deposition, through a combination of targeting strategies could be the future direction for the treatment of lung pathologies through the pulmonary route.

Developing inhaled protein therapeutics for lung diseases

“…Larger size particles will generally be deposited in the oropharyngeal region and be ingested, while small particles < 1 μm may be exhaled during the next breathing cycle. Thus, suitable aerosol particle sizes need to be selected for precise drug delivery into the lung to enhance drug efficacy while simultaneously reducing harmful side effects [ 5 ].…”

“…The second clearance mechanism is macrophage uptake, which is the primary clearance mechanism in the alveoli. Proteins are taken up by alveolar macrophages in the deep lung via pinocytosis, and the uptake of particles is size dependent [ 5 , 12 , 62 ]. Large proteins (≥ 40 kDa) would have more time to be engulfed by alveolar macrophages by virtue of their slower transport and absorption across the alveolo-capillary barrier, while small proteins and peptides (≤ 25 kDa) are absorbed rapidly from the airspaces and thus, may not be impacted by alveolar macrophage uptake as much.…”

“…In addition, proteins and other macromolecules have the potential to induce immunogenicity, with the production of anti-drug antibodies (ADAs) as the main immune response [ 5 ]. The development of ADAs in patients can alter pharmacokinetics, drastically reduce efficacy, and can also lead to severe adverse events or even lethal consequences [ 76 ].…”

“…Nevertheless, there are strategies that can be employed to increase the local residence time of protein therapeutics in the lungs, and these will be discussed in detail later on in this review. Besides improving pharmacokinetic and toxicity profiles of protein therapeutics, the inhalation route is non-invasive and allows for self-administration, which could improve patient compliance [ 4 , 5 , 12 ].…”

Nanoparticle Technology for Respiratory Tract Mucosal Vaccine Delivery

“…Pulmonary vaccine delivery required particle and droplet sizes below 5µm (Hickey A.J., 2004). Nebulized droplets containing nanoparticles or dry micro-aggregated particles can be used to deliver vaccines to the pulmonary mucosa (Osman N. et al, 2018).…”