Introduction: Inhalation has consistently been acknowledged as an optimal delivery method due to its higher local concentration, patient-friendliness etc. However, the mucus clearance in the airways is a barrier for inhaled drugs. Cilia, which move freely, enable continuous mucus flow, to trap and remove inhaled particles. Consequently, there is limited opportunity for inhaled drugs to be taken up by cells under the mucus. As a result, there is a growing need to facilitate the entry of inhaled drugs into the body against mucus clearance. Despite extensive efforts to improve inhaled drug retention through methods like formula modifications of lipid nanoparticles, molecular design, and targeted strategies, effectiveness remains elusive.
In this study, Inhalable Bio-adhesive Hydrogel for Enhanced Lung-mucus Penetration, referred to Bio-HELP, has been developed as a platform adjuvant to enhance retention of drugs across various categories. Upon inhaling bio-HELP microparticles with model drugs, Bio-HELP will swell upon contacting the mucus due to its hydrogel nature. Then the polymer network delivered by hydrogel will expand and form covalent bonds with amino groups in mucins in mucus and cilia on epithelial cells. Therefore, the network physically restricts the movement of mucin, devastating mucus clearance, finally prolonging drug retention before it finally degrades 48h later.
Materials and
Methods: bio-HELP particles were prepared using a water‐in‐oil emulsion method. One gram gelatin was dissolved in 5ml ultrapure water with 3ml acrylic acid. This prepared solution was added to oil with 0.1 wt.% Tween. The mixture was stirred in an ice-water bath for 2 h. To obtain the SHIELD particles, the mixture was filtered and washed with acetone.
Results, Conclusions, and Discussions:
Results:
In this study, we established three models representing different diseases to evaluate the efficacy of the platform adjuvant bio-HELP in delivering three types of drugs, ranging from molecules to nanoparticles.
1. Within the lung cancer model, the clinically utilized first-line drug carboplatin was administered via inhalation with bio-HELP. This delivery method resulted in a significant reduction in tumor size compared to inhalation without bio-HELP. Furthermore, compared to intravenous administration of carboplatin at a higher dose, inhalation-based chemotherapy significantly improved survival rates with minimal systemic side effects.
2. In the pulmonary fibrosis model, bexotegrast, currently undergoing Phase 2 clinical trials, was delivered via inhalation with bio-HELP. When compared to both inhalation-only and orally administered bexotegrast of higher dose, the combination of bexotegrast with bio-HELP demonstrated superior therapeutic efficacy, as evidenced by reduced cytokine concentrations and improved physiological structures.
3. Within the SARS-CoV-2 model, LNP-mRNA-1273, developed by Moderna, was delivered via inhalation with bio-HELP as a potential COVID vaccine. Compared to inhalation without bio-HELP and intramuscular injection of LNP-mRNA, inhalation with bio-HELP resulted in a stronger immune response including mucosal immunity and systemic immunity, as indicated by higher levels of IgA in bronchoalveolar lavage fluid and IgG in serum. Additionally, the SARS-CoV-2 pseudovirus model confirmed the enhanced defense provided by LNP-mRNA in conjunction with bio-HELP.
Conclusions and Discussions:
By temporarily slowing down mucus clearance in 48h through the polymer network formed on mucin and cilia, bio-HELP significantly reduces the speed of mucus clearance, thereby enhancing the retention of inhaled drugs. Consequently, bio-HELP facilitates the inhalation of drugs ranging from molecules to nanoparticles, which were originally administered intravenously, orally, or intramuscularly. This expansion enables the advantages of inhalation to be extended to a wider range of drugs without any modification, including significantly lower dosages, minimal systemic side effects, reduced risk of first-pass metabolism, and needle-free administration, among others.
.jpg "Savannah (Weihang) Zhang, BA (they/them/theirs) photo")
