Sustained release of a low molecular weight antilipolytic drug from an electroactive hydrogel for antiaging and biomedical applications

Abstract

Premature aging has evolved as one of the major clinical concerns globally because it reduces the working ability of human beings. Therefore, this work demonstrated the delaying of the aging process via sustained delivery of a low-molecular weight (MW) antilipolytic drug, 3,5-dimethylpyrazole (DMP, MW = 96.13 g mol⁻¹). Eventually, the sustained release of DMP is challenging due to rapid clearance, limiting therapeutic efficacy in metabolic disorders. Herein, we developed a DMP-encapsulated-chitosan-grafted-terpolymer (poly[itaconic acid-co-2-ethyl-2-((N-isopropylbutyramido)methyl)succinic acid-co-N-isopropylacrylamide) hydrogel (DCBH) through multi-stage statistical optimization for the sustained delivery of DMP. The mechanically robust DCBH successfully achieved 15-day sustained release of DMP following first-order kinetics, despite its low MW. DCBH demonstrated superior mechanical properties with an ultimate tensile strength of 697 ± 11.05 kPa and multifunctional therapeutic capabilities including significant antioxidant activity (88.38% H₂O₂ scavenging), antibacterial efficacy against S. aureus (inhibition zone: 3.31 ± 0.46 cm), electrical conductivity matching human skin (0.014-1.9 mS cm⁻¹), and Fe²⁺-chelation ability. Glucose consumption assay revealed potential metabolic regulatory effects, while cell studies showed enhanced migration (95.47% vs. 26.15% control), F-actin organization, and excellent biocompatibility with NIH3T3 cells. Senescence associated-β-galactosidase (SA-β-Gal) staining on NIH3T3 cells indicated DCBH's efficiency in combating cellular senescence and premature aging. The electroactivity of DCBH can facilitate cellular proliferation, migration, and angiogenesis through electrical stimulation, while contributing to cellular homeostasis maintenance via recycling of damaged cytoplasmic constituents. This multifunctional platform addresses the challenge of sustained delivery for low-MW therapeutics while providing synergistic therapeutic properties for comprehensive antiaging and biomedical applications.