Novel drug delivery systems targeting oxidative stress in chronic obstructive pulmonary disease: a review

Abstract

Oxidative stress is significantly involved in the pathogenesis and progression of chronic obstructive pulmonary disease (COPD). Combining antioxidant drugs or nutrients results in a noteworthy therapeutic value in animal models of COPD. However, the benefits have not been reproduced in clinical applications, this may be attributed to the limited absorption, concentration, and half-life of exogenous antioxidants. Therefore, novel drug delivery systems to combat oxidative stress in COPD are needed. This review presents a brief insight into the current knowledge on the role of oxidative stress and highlights the recent trends in novel drug delivery carriers that could aid in combating oxidative stress in COPD. The introduction of nanotechnology has enabled researchers to overcome several problems and improve the pharmacokinetics and bioavailability of drugs. Large porous microparticles, and porous nanoparticle-encapsulated microparticles are the most promising carriers for achieving effective pulmonary deposition of inhaled medication and obtaining controlled drug release. However, translating drug delivery systems for administration in pulmonary clinical settings is still in its initial phases.

Keywords: Chronic obstructive pulmonary disease; Drug delivery; Microparticles; Nanocomposite microparticles; Nanoparticles; Oxidative stress.

Fig. 1

Sources of ROS and differences between a healthy lung and a lung with COPD

Fig. 2

Cigarette smoke-related vascular irritation and activation in patients with COPD. Oxidative irritants including tobacco smoke have a direct effect on the epithelial cells, macrophages, and oedematous basal membranes. The airway smooth muscle markedly increased under excess exposure to ROS. Irritants activate macrophages to release several chemotactic factors including CCL2, which attract inflammatory cells to the lungs and acts on CCR2 to attract monocytes. LTB, CXCL1, and CXCL8 act on CCR2 to attract neutrophils. Neutrophil elastase causes hypersecretion of mucus. CXCL9, CXCL10, and CXCL11 act on CXCR 3, which attracts T_H1 and T_C 1 cells. T_C1 cells, through the release of perforin and granzyme B, induce apoptosis of type I pneumocytes, thereby contributing to emphysema. IFNγ and TNFα released by T_H1 stimulate inflammation. Activated macrophages provide oxidative signalling to neutrophils and T_H1 cells, which cause an imbalance in the protease/antiprotease system and overexpression of MMP-9 and Ne. The increased expression of Ne induces TNF-α by the NF-κB signalling pathway and accelerates apoptosis of epithelial cells. Oxidative stress activates P13K leading to the phosphorylation and inactivation of HDAC2. Macrophages generate ROS and NO that form ONOO-peroxynitrite and might also inhibit the activity of HDAC2. These modifications of HDAC2 result in corticosteroid resistance in COPD patients. Oxidative stress also drives accelerated ageing through the activation of P13K and reduction in sirtuin-1 levels, which leads to cellular senescence and release of inflammatory proteins, further increasing oxidative stress. ROS can induce tachykinin release from the capsaicin-sensitive sensory that acts on the neurokinin receptors in the airways to induce bronchial hyperresponsiveness. P13K, phosphoinositide 3-kinase; IL, interleukin; TGF, transforming growth factor; MMP, matrix metalloproteinase; MUC5AC; Ne, neutrophil elastase; ROS, reactive oxygen species; CCL, CC-chemokine ligand; CCR, CC-chemokine receptor; CXCL, CXC-chemokine ligand; CXCR, CXC-chemokine receptor; T_H1, T helper1 cells; T_C1, type 1 cytotoxic; NO, nitric oxide; ONOO⁻, peroxynitrite

Fig. 3

Representative nanoparticles and microparticles used for delivering antioxidants in COPD

Fig. 4

Manufacturing methods, jet milling, spray drying, spray freeze drying and SFD, of preparing microparticles and their deposition mechanism

Fig. 5

Morphology of A microscale dry powder [180]; B porous microparticles [170]; C matrix NCMPs [181]; D hollow NCMPs [182]

Fig. 6

Preparation of nanocomposite microparticle and their reconstitution

Fig. 7

What happens to an aerosol drug after deposition in the lungs? (modified from [187])