Mucin-mediated mucosal retention via end-terminal modified Pluronic F127-based hydrogel to increase drug accumulation in the lungs

Tsung-Yun Wu; Chun-Chiang Huang; Hsieh-Chih Tsai; Tzu-Kai Lin; Pei-Yu Chen; Haile Fentahun Darge; Zhen-Xiang Hong; Horng-Jyh Harn; Shinn-Zong Lin; Juin-Yih Lai; Yu-Shuan Chen

doi:10.1016/j.bioadv.2023.213722

Mucin-mediated mucosal retention via end-terminal modified Pluronic F127-based hydrogel to increase drug accumulation in the lungs

Biomater Adv. 2024 Jan:156:213722. doi: 10.1016/j.bioadv.2023.213722. Epub 2023 Dec 5.

Authors

Affiliations

¹ Graduate Institute of Applied Science and Technology, National Taiwan University of Science and Technology, Taipei 106, Taiwan, ROC.
² Taiwan Instrument Research Institute, National Applied Research Laboratories, Hsinchu 302, Taiwan, ROC.
³ Graduate Institute of Applied Science and Technology, National Taiwan University of Science and Technology, Taipei 106, Taiwan, ROC; Advanced Membrane Materials Center, National Taiwan University of Science and Technology, Taipei 106, Taiwan, ROC; R&D Center for Membrane Technology, Chung Yuan Christian University, Chungli, Taoyuan 320, Taiwan, ROC. Electronic address: h.c.tsai@mail.ntust.edu.tw.
⁴ Department of Dermatology, Skin Institute, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970, Taiwan, ROC; Department of Dermatology, School of Medicine, Tzu Chi University, Hualien 970, Taiwan, ROC.
⁵ Bioinnovation Center, Buddhist Tzu Chi Medical Foundation, Hualien 970, Taiwan, ROC.
⁶ Centre for Ocular Research & Education (CORE), School of Optometry and Vision Science, University of Waterloo, 200 University Avenue West, Waterloo, ON N2L 3G1, Canada.
⁷ Bioinnovation Center, Buddhist Tzu Chi Medical Foundation, Hualien 970, Taiwan, ROC; Centre for Ocular Research & Education (CORE), School of Optometry and Vision Science, University of Waterloo, 200 University Avenue West, Waterloo, ON N2L 3G1, Canada; Department of Pathology, Hualien Tzu Chi Hospital, Tzu Chi University, Buddhist Tzu Chi Medical Foundation, Hualien 970, Taiwan, ROC.
⁸ Bioinnovation Center, Buddhist Tzu Chi Medical Foundation, Hualien 970, Taiwan, ROC; Department of Neurosurgery, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970, Taiwan, ROC.
⁹ Graduate Institute of Applied Science and Technology, National Taiwan University of Science and Technology, Taipei 106, Taiwan, ROC; Advanced Membrane Materials Center, National Taiwan University of Science and Technology, Taipei 106, Taiwan, ROC; R&D Center for Membrane Technology, Chung Yuan Christian University, Chungli, Taoyuan 320, Taiwan, ROC; Department of Chemical Engineering and Materials Science, Yuan Ze University, Chungli, Taoyuan 320, Taiwan, ROC.
¹⁰ Bioinnovation Center, Buddhist Tzu Chi Medical Foundation, Hualien 970, Taiwan, ROC; Department of Medical Research, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970, Taiwan, ROC; Tzu Chi University of Science and Technology, Hualien 970, Taiwan, ROC. Electronic address: yschen0130@tzuchi.com.tw.

PMID: 38101076
DOI: 10.1016/j.bioadv.2023.213722

Abstract

Noninvasive lung drug delivery is critical for treating respiratory diseases. Pluronic-based copolymers have been used as multifunctional materials for medical and biological applications. However, the Pluronic F127-based hydrogel is rapidly degraded, adversely affecting the mechanical stability for prolonged drug release. Therefore, this study designed two thermosensitive copolymers by modifying the Pluronic F127 terminal groups with carboxyl (ADF127) or amine groups (EDF127) to improve the viscosity and storage modulus of drug formulations. β-alanine and ethylenediamine were conjugated at the terminal of Pluronic F127 using a two-step acetylation process, and the final copolymers were characterized using ¹H nuclear magnetic resonance (¹H NMR) and Fourier-transform infrared spectra. According to the ¹H NMR spectra, Pluronic F127 was functionalized to form ADF127 and EDF127 with 85 % and 71 % functionalization degrees, respectively. Rheological studies revealed that the ADF127 (15 wt%) and EDF127 (15 wt%) viscosities increased from 1480 Pa.s (Pluronic F127) to 1700 Pa.s and 1800 Pa.s, respectively. Furthermore, the elastic modulus of ADF127 and EDF127 increased, compared with that of native Pluronic F127 with the addition of 5 % mucin, particularly for ADF127, thereby signifying the stronger adhesive nature of ADF127 and EDF127 with mucin. Additionally, ADF127 and EDF127 exhibited a decreased gelation temperature, decreasing from 33 °C (Pluronic F127 at 15 wt%) to 24 °C. Notably, the in vitro ADF127 and EDF127 drug release was prolonged (95 %; 48 h) by the hydrogel encapsulation of the liposome-Bdph combined with mucin, and the intermolecular hydrogen bonding between the mucin and the hydrogel increased the retention time and stiffness of the hydrogels. Furthermore, ADF127 and EDF127 incubated with NIH-3T3 cells exhibited biocompatibility within 2 mg/mL, compared with Pluronic F127. The nasal administration method was used to examine the biodistribution of the modified hydrogel carrying liposomes or exosomes with fluorescence using the IVIS system. Drug accumulation in the lungs decreased in the following order: ADF127 > EDF127 > liposomes or exosomes alone. These results indicated that the carboxyl group-modified Pluronic F127 enabled well-distributed drug accumulation in the lungs, which is beneficial for intranasal administration routes in treating diseases such as lung fibrosis.

Keywords: Adhesive nature; Carboxyl groups; Drug delivery; Nasal administration; Respiratory diseases; Thermosensitive copolymer.

MeSH terms

Animals
Hydrogels
Liposomes*
Lung
Mice
Mucins
Poloxamer* / chemistry
Polymers
Tissue Distribution

Substances

Poloxamer
Liposomes
Hydrogels
Mucins
Polymers