Pulmonary delivery of magnolol-loaded nanostructured lipid carriers for COPD treatment

Chronic obstructive pulmonary disease (COPD) is a prevalent condition characterized by persistent airflow restriction and associated with chronic inflammation and lung parenchyma (Vanfleteren et al., 2016, Willer et al., 2021). The global prevalence of COPD is estimated to range from 9 % to 12 %, defined by the Global Initiative for COPD criteria of a forced expiratory volume during the first second of forced breath (FEV1) / forced vital capacity (FVC) < 0.7(Boers et al., 2023). This translates to a significant global burden, affecting an estimated 300 to 400 million individuals (Chen et al., 2022), thereby making COPD a major global health concern and one of the leading causes of death worldwide (Li et al., 2023). Diagnosis of COPD typically involves a comprehensive assessment to exclude other potential causes of airflow limitation, particularly in individuals with a history of tobacco smoking. Additional contributing factors include exposure to air pollutants, dust, chemicals, particulate matter, and wood smoke, which may enhance the risk of developing COPD (Lenoir and Quint, 2022).

Chronic cigarette smoke inhalation is widely recognized as a primary inducer of COPD, leading to chronic inflammation of the airways and lung parenchyma. This inflammatory process involves a multitude of pro-inflammatory mediators, involving several conventional and atypical pro-inflammatory mediators including cytokines, chemokines, growth factors, reactive oxygen species (ROS) and matrix metalloproteinases that are maintained by aberrant recruitment and activation of several immune cells also increasing the risk of lung infections (D’Anna et al., 2020). Cigarette smoke contains high levels of oxidative agents that directly stimulate the generation of endogenous ROS in various cell types, including epithelial cells, macrophages, and edematous basement membranes. Excessive ROS production triggers the activation of endogenous antioxidant mechanisms to counteract oxidative stress, which significantly contributes to the pathogenesis of COPD. Current treatments for COPD typically involve glucocorticoids, anticholinergic drugs, and ß2 agonists (Uwagboe et al., 2022). However, these medications exhibit limited efficacy and often induce side effects such as rash, tachycardia, dizziness, metabolic disturbances, and psychiatric disorders. Furthermore, they predominantly serve to alleviate symptoms rather than addressing the underlying disease mechanisms.

In clinical practice, traditional Chinese medicine (TCM) plays a significant role in managing COPD (Liu et al., 2023, Yang et al., 2020). Magnolol (MA), a bioactive compound derived from Magnolia officinalis Rehder et Wilson, has demonstrated potential in COPD management due to its multifunctional activities. Research by Zhang et al. highlights MA’s anti-inflammatory properties by upregulating peroxisome proliferator-activated receptor gamma (PPAR γ) expression while inhibiting the NF-κB signaling pathway, cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS). These mechanisms reduce reactive oxygen species (ROS) production, thereby improving lung edema and decreasing neutrophil infiltration, common in COPD exacerbations (Zhang et al., 2019). Furthermore, Niu et al. discuss MA’s impact on transient receptor potential vanilloid 4 (TRPV4), crucial in regulating pulmonary fibrosis—a frequent complication in COPD. MA has shown promise in alleviating pulmonary fibrosis by targeting TRPV4, suggesting its potential to mitigate fibrotic changes and preserve lung function in COPD patients (Niu et al., 2023). However, MA’s poor water solubility limits its bioavailability and clinical efficacy (Lin et al., 2021). Current MA administration methods typically involve oral or injected forms, often necessitate the use of dimethyl sulfoxide (DMSO) as a solvent potentially increasing the risk of adverse effects (Galvao et al., 2014). Several researchers have focused on improving MA’s solubility through formulation techniques. Although some dosage forms have shown improved bioavailability to some extent, enhancements in drug dissolution and bioavailability remain limited.

Pulmonary drug delivery is a pivotal area of research, particularly for conditions such as COPD, where precise and efficient medication delivery to the lungs is crucial for effective treatment. Nanostructured lipid carriers (NLCs) have proven to be successful in delivering therapeutics via pulmonary inhalation, showcasing their versatility and effectiveness (Majumder and Minko, 2021). The unique attributes of NLCs, including high biocompatibility and excellent drug-loading capacity, position them as ideal candidates for pulmonary drug delivery systems (Wang et al., 2022). For instance, a study on the pulmonary delivery of hydroxychloroquine using nanostructured lipid carriers for potential COVID-19 treatment underscores the importance of targeted lung drug delivery in managing respiratory conditions effectively (Ali et al., 2022). Additionally, research on mannose-functionalized isoniazid-loaded NLCs for pulmonary delivery highlights NLCs’ potential to target specific receptors on lung cells, enhancing therapeutic efficacy (Ahalwat et al., 2023). Researchers have investigated the encapsulation of various drugs in NLCs for effective pulmonary delivery, showing promising results in terms of biocompatibility and therapeutic efficacy (Huguet-Casquero et al., 2020). Despite these advances, it is noteworthy that, no current research is available on inhalable pulmonary delivery formulations integrating MA, a gap that warrants further exploration in light of MA’s potential therapeutic benefits.

Inhalation with nebulizer is a method of drug delivery that administers medications to the pulmonary area as an aerosol, offering advantages such as reduced irritation to the respiratory tract, rapid drug absorption, and quick onset of action (Wu and Zhang, 2023). Nebulizers are commonly used in aerosol therapy for patients with pulmonary diseases, providing an effective means of drug delivery (Nguyen et al., 2020). This delivery method has been particularly beneficial in delivering medications to the lungs with high bioavailability through a noninvasive route (Hao-Yang et al., 2022). In this study, we encapsulated MA as a model drug in nanostructured lipid carriers (MA-NLC) using emulsification and solvent evaporation. The quality of MA-NLC was evaluated through assessments of particle size, zeta potential, morphology, encapsulation efficiency, drug loading, X-ray powder diffraction, and Fourier transform infrared spectroscopy. We elucidated the feasibility and rationale for employing MA-NLC for pulmonary delivery in COPD treatment through biodistribution, pharmacodynamics, and pharmacokinetics studies.

Materials

Materials utilized in this study included MA (G2128108, Aladdin Holdings Group Co., Ltd., Shanghai, China); Dexamethasone acetate tablets (H12020122, Tianjin Lisheng Pharmaceutical Co., Ltd., Tianjin, China); Compritol 888 ATO (108833, Gattefossé, St. Priest, France); Soybean phospholipids (SY-SI-180101, A.V.T. Pharmaceutical Co., Ltd., Shanghai, China); Myrij52, Dihydroethidium, and LPS (MKBV6365V, D7007, L2880, Sigma, Missouri, USA); Miglyol 812 (IOI Oleo)

Read more

Bei Jia, Jiachen He, Ying Zhang, Wenli Dang, Bin Xing, Mengru Yang, Haonan Xie, Jiawei Li, Zhidong Liu, Pulmonary delivery of magnolol-loaded nanostructured lipid carriers for COPD treatment, International Journal of Pharmaceutics, Volume 662, 2024, 124495, ISSN 0378-5173,
https://doi.org/10.1016/j.ijpharm.2024.124495.