The Potential of α-Mangostin-Loaded Chitosan/Collagen Nanoparticles in Hydrogel Formulation for Enhanced Wound Healing

Kusnadi,1,2 Yedi Herdiana,3 Emma Rochima,4 I Made Joni,5,6 Okta Nama Putra,1,7 Amirah Mohd Gazzali,8 Muchtaridi Muchtaridi3,9 1Doctoral Program of Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Sumedang, 45363, Indonesia; 2Department of Pharmacy, Universitas Harkat Negeri, Tegal, Central Java, 52147, Indonesia; 3Department of Pharmaceutical Analysis and Medicinal Chemistry, Faculty of Pharmacy, Universitas Padjadjaran, Sumedang, 45363, Indonesia; 4Department of Fishery, Faculty of Fisheries and Marine Sciences, Universitas Padjadjaran, Sumedang, 45363, Indonesia; 5Functional Nano Powder University Center of Excellence (Finder u Coe), Universitas Padjadjaran, Sumedang, 45363, Indonesia; 6Departement of Physics, Faculty of Mathematics and Natural Sciences, Universitas Padjadjaran, Sumedang, 45363, Indonesia; 7Research Center for Agroindustry – National Research and Innovation Agency (BRIN), Cibinong, Indonesia; 8School of Pharmaceutical Sciences, Universiti Sains Malaysia, Gelugor, Penang, 11800, Malaysia; 9Research Collaboration Centre for Radiopharmaceuticals Theranostic, National Research and Innovation Agency (BRIN), Sumedang, 45363, IndonesiaCorrespondence: Muchtaridi Muchtaridi, Department of Pharmaceutical Analysis and Medicinal Chemistry, Faculty of Pharmacy, Universitas Padjadjaran, Jl. Ir.Soekarno KM 21, Sumedang, 45363, Indonesia, Tel +62-813-9449-5569, Email [email protected]: Chronic and acute wounds remain difficult to manage due to the inability of conventional dressings to provide sustained delivery of poorly soluble bioactives such as α-mangostin. This study investigates the potential of α-mangostin (AMG)-loaded chitosan/collagen nanoparticles (AMG-Ch/Coll NPs) incorporated into a hydrogel system for enhanced topical wound healing.Methods: Nanoparticles were prepared by ionic gelation and characterized for particle size, zeta potential, morphology (SEM), entrapment efficiency, and physicochemical interactions (FTIR, XRD, DSC). AMG solubility, including its apparent solubility in AMG–Ch NPs and AMG–Ch/Coll NPs was quantified. Subsequently, hydrogels incorporating AMG, AMG–Ch NPs, AMG–Ch/Coll NPs, and Ch–Coll NPs were formulated and evaluated for pH, spreadability, swelling ratio, and in vitro drug release. In vivo wound-healing efficacy was further assessed using a rat excision model.Results: Mean particle size increased from 297.10 ± 11.64 nm (AMG–Ch NPs) to 317.66 ± 8.76 nm (AMG–Ch/Coll NPs) and 339.62 ± 6.43 nm (Ch–Coll NPs), indicating the influence of collagen on particle size. FTIR, XRD, and DSC analyses confirmed the successful formation of amorphous nanoparticles with strong intermolecular interactions, contributing to enhanced structural stability and solubility. A fourfold improvement in AMG solubility was observed in the nanoparticle formulations, which were subsequently incorporated into hydrogel matrices and evaluated for topical application. All hydrogel (HG) formulations exhibited acceptable pH values (6.50– 6.98) suitable for skin application. AMG-Ch NPs-HG demonstrated superior spreadability, swelling ratio, and drug release profiles, followed by AMG-Ch/Coll NPs-HG. Sustained AMG release was achieved, supporting prolonged bioavailability. In vivo wound healing studies in rats revealed that AMG-Ch NPs-HG and AMG-Ch/Coll NPs-HG significantly accelerated wound closure (99.28 ± 3.59% and 98.13 ± 3.26%, respectively, on day 21), outperforming AMG-HG (89.12 ± 2.58%), Ch/Coll NPs-HG (88.95 ± 3.14%), and the control group (79.84 ± 2.25%).Conclusion: Overall, these findings highlight the synergistic advantages of AMG-loaded Ch/Coll NPs in hydrogel formulations as a promising platform for enhanced topical wound healing. Keywords: α-mangostin, ionic gelation, particle size, in vitro drug release, wound closure