Mucosal Penetrative Polymeric Micelle Formulations for Insulin Delivery to the Respiratory Tract
Abstract
Purpose: Effective mucosal delivery of drugs continues to pose a significant challenge owing to the formidable barrier presented by the respiratory tract mucus, which efficiently traps and clears foreign particulates. The surface characteristics of micelles dictate their ability to penetrate the respiratory tract mucus. In this study, polymeric micelles loaded with insulin (INS) were modified using mucus-penetrative polymers.
Methods: We prepared and compared polyethylene glycol (PEG)-coated micelles with micelles where cell-penetrating peptide (CPP) is conjugated to PEG. Systematic investigations of the physicochemical and aerosolization properties, performance, in vitro release, mucus and cell penetration, lung function, and pharmacokinetics/pharmacodynamics (PK/PD) of polymeric micelles were performed to evaluate their interaction with the respiratory tract.
Results: The nano-micelles, with a particle size of < 100 nm, exhibited a sustained-release profile. Interestingly, PEG-coated micelles exhibited higher diffusion and deeper penetration across the mucus layer. In addition, CPP-modified micelles showed enhanced in vitro cell penetration. Finally, in the PK/PD studies, the micellar solution demonstrated higher maximum concentration (Cmax) and AUC0-8h values than subcutaneously administered INS solution, along with a sustained blood glucose-lowering effect that lasted for more than 8 h.
Conclusion: This study proposes the use of mucus-penetrating micelle formulations as prospective inhalation nano-carriers capable of efficiently transporting peptides to the respiratory tract.
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Materials
NS and rhodamine-B were purchased from Sigma-Aldrich (Sydney, Australia). Soluplus (Polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer [PCL-PVAc-PEG]) was purchased from BASF (Ludwigshafen, Rhineland-Palatinate, Germany). DPPE-PEG 2k and 5k was purchased from Biopharma (Watertown, MA, USA). DPPE-PEG-CPP was synthesized using an amine-ester reaction, which is commonly used for PEGylation or peptide conjugation.2,22 (Figure 2). The Calu-3 and A549 cell line were purchased from American Type Cell Culture Collection (ATCC, Rockville, MD, USA). Dulbecco’s modified Eagle’s medium (DMEM, without phenol red and L-glutamine), penicillin–streptomycin (10,000 U/mL), fetal bovine serum (FBS), phosphate-buffered saline (PBS), Hanks balanced salt solution (HBSS), and 0.25% trypsin-EDTA were purchased from Gibco® (New York, NY, USA). Transwell® cell culture inserts (0.33 cm2 polyester membrane, 0.4 µm pore size) and T-75 cell culture flasks were purchased from Corning Costar® (Lowell, MA, USA). The experimental animals (8-week-old, male, Sprague-Dawley rats) were purchased from Samtaco Bio Co. (Osan, Korea). High-performance liquid chromatography (HPLC)-grade trifluoroacetic acid (TFA), ethanol, and acetonitrile (ACN) were used (Honeywell Burdick & Jackson, Muskegon, MI, USA). All other reagents were of analytical or HPLC grade.
Kang JH, Jeong JH, Kwon YB, Kim YJ, Shin DH, Park YS, Hyun S, Kim DW, Park CW. Mucosal Penetrative Polymeric Micelle Formulations for Insulin Delivery to the Respiratory Tract. Int J Nanomedicine. 2024;19:9195-9211
https://doi.org/10.2147/IJN.S474287
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