Incipient need of targeting airway remodeling using advanced drug delivery in chronic respiratory diseases

Meenu Mehta1,2, Saurabh Satija*,1,3 , Keshav R Paudel2,4, Gang Liu2,4, Dinesh K Chellappan5, Philip M Hansbro2,4 & Kamal Dua**,1,2,6,7 1Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, NSW 2007, Australia 2Center for Inflammation, Centenary Institute, Sydney, NSW 2050, Australia 3School of Pharmaceutical Sciences, Lovely Professional University, Phagwara 144411, Punjab, India 4School of Life Sciences, University of Technology Sydney, Ultimo, NSW 2007, Australia 5Department of Life Sciences, School of Pharmacy, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia 6Priority Research Centre for Healthy Lungs, University of Newcastle & Hunter Medical Research Institute, Lot 1 Kookaburra Circuit, New Lambton Heights, Newcastle, NSW 2305, Australia 7School of Pharmaceutical Sciences, Shoolini University, Solan, Himachal Pradesh 173229, India *Author for correspondence: Saurabh.Satija@uts.edu.au **Author for correspondence: Kamal.Dua@uts.edu.au

Commentary Mehta, Satija, Paudel et al. bronchial portions and subsegmental walls have their whole dimensions thickened [8]. In COPD, only the inner wall of the major airways is thicker and more persuasive. The peripheral airways are often distinctly remodeled in COPD, typically free of cartilage or bronchial tissue [9,10].

Advanced drug delivery for regeneration
Like most airway remodeling, transient airflow obstructions, caused by inflammation, mucus spikes and bronchial hyper-reactiveness are associated with CRDs, for instance. Given the present care and management choices, a substantial number of patients remain poorly managed for such diseases, namely, asthma and COPD, which are usually triggered by a respiratory virus infection. As a result, new innovative drug therapies remain important in order that exacerbations can be better managed and avoided. Thus, various advanced therapies have been developed in the field of drug delivery in respiratory diseases such as nanoparticles (NPs), including extracellular vesicles and their synthetic equivalents [11].
Ideally, these new therapeutic strategies are focused on the activation of the regenerative capacity of the lung itself. Understanding the various pathways and the targeted delivery of drugs that initiate, sustain, modulate, and conclude normal lung development could be essential to new regenerative approaches by reactivating pulmonary disease pathways [12].
Targeted advanced drug-delivery strategies can provide increased accumulation, greater effectiveness and enhanced protection. Gabriela et al. recently coupled an anti-fibrotic small molecule (αPV1) with an anti-PV1 antibody and reported a substantial reduction in lung fibrosis in idiopathic pulmonary fibrosis, compared with an isotype controlled antibody [13]. Juan et al. made ATG101 single-stranded antisense RNA-loaded DNA triangular NPs (ssATG101-TNP) to knock down expression of the ATG101 gene. They demonstrated that ssATG101-TNP can efficiently be transfected into human pulmonary arterial endothelial cells in a time and dose-dependent manner, and knockdown of ATG101 stimulates the cell apoptosis and inhibits hypoxic cell autophagy and proliferation as a possible therapeutic goal for endothelial injury related conditions [14]. In scleroderma associated interstitial lung disease (SSc-ILD), patients with derived cells in an experimental lung fibrosis model, were administered with imatinib loaded gold nanoparticles (GNPs). GNPs were synthesized using anti-CD44 and were loaded with imatinib (GNP-HCIm). Patients with scleroderma associated interstitial lung disease were diagnosed with lung fibroblast and alveolar macrophages in the presence of NPs from bronchoalveolar lavage fluids. Their research showed that the GNP-HCIm significantly inhibited proliferation and viability inducing apoptosis of LFs and effectively reduced IL-8 release, viability and M2 polarization in alveolar macrophages. [15]. Tsai et al. reported that cerium dioxide NPs can reduce Ca 2+ cytosolic change and TiO 2 NP-induced mitochondrial damage. Their team presented evidence that TiO 2 NPs can attenuate hypersecretion and apoptosis progression [16]. In a most recent study conducted by Chattopadhyay et al., atropine nanoparticles (ANPs) have been shown to suppress inflammatory cytokines, reduce shallow breathing and normalize the hyper-responsiveness of the tidal tissue and obstructed lungs. Moreover, treatment with ANP reduced progressive blockage of the airway and decreased deposition of collagens. Thus, ANP strengthens the airway surfaces of the lung and reduces lung hyperaction, blockage and inflammation [17]. Lou et al. showed the significance of miRNA in airway remodeling. It was shown that miR-192-5p had an overexpressed effect in the smooth muscle cells in airways. In addition, in vitro and in vivo asthma mice demonstrated a similar effect which was shown to be the effect of miR-192-5p on proliferation [18]. Prior to this, various other studies have also reported the potential of miRNA in tissue regeneration. Simeoli et al. in their research showed that the delivery of LNA-based anti-miR21 and anti-miR-712 in mouse models of atherosclerosis and nerve trauma reduced the inflammatory macrophage number through liposomes or cationic lipids-coated NPs [19,20]. All of these evidences in one way or other, state that the combinations of the different targeted approach contribute to the drug research and development for airway tissue regeneration.

Conclusion
Advancements in the field of drug delivery, particularly NPs, is providing an extra edge in combating the emerging complications of airway remodeling in chronic respiratory diseases. Considering the fact that remodeling worsens the respiratory disease pathology, it is an emerging and demanding area of research to be explored by translational, clinical and drug-delivery scientists to provide a new direction to the pulmonary clinics especially during the current, complex and uncertain times of global pandemic situation.