RESUMEN
Oral ulceration is the most common oral mucosal disease. Oral mucosal ulcers are extremely painful, may interfere with eating and speaking, and potentially complicate systemic symptoms in severe cases. The humid and highly dynamic environment of the oral cavity makes local drug administration for treating oral mucosal ulcers challenging. To overcome these challenges, we designed and prepared a novel dissolving microneedle (MN) patch containing multiple drugs in a core-shell to promote oral ulcer healing. The MNs contained a methacrylate gelatin shell layer of basic fibroblast growth factor (bFGF), a hyaluronic acid (HA) core loaded with dexamethasone (DXMS), and zeolite imidazoline framework-8 (ZIF-8) encapsulated in the HA-based backplane. Progressive degradation of gelatin methacryloyl (GelMA) from the tip of the MN patch in the oral mucosa resulted in sustained bFGF release at the lesion site, significantly promoting cell migration, proliferation, and angiogenesis. Moreover, the rapid release of HA and, subsequently, DXMS inhibited inflammation, and the remaining MN backing after the tip dissolved behaved as a dressing, releasing ZIF-8 for its antimicrobial effects. This novel, multifunctional, transmucosal core-shell MN patch exhibited excellent anti-inflammatory, antimicrobial, and pro-healing effects in vivo and in vitro, suggesting that it can promote oral ulcer healing.
Asunto(s)
Gelatina , Ácido Hialurónico , Metacrilatos , Mucosa Bucal , Agujas , Úlceras Bucales , Cicatrización de Heridas , Ácido Hialurónico/química , Gelatina/química , Animales , Úlceras Bucales/tratamiento farmacológico , Úlceras Bucales/patología , Mucosa Bucal/efectos de los fármacos , Mucosa Bucal/metabolismo , Metacrilatos/química , Cicatrización de Heridas/efectos de los fármacos , Ratas , Dexametasona/administración & dosificación , Dexametasona/farmacología , Factor 2 de Crecimiento de Fibroblastos/administración & dosificación , Masculino , Ratones , HumanosRESUMEN
Synergistic anti-tumor effect of anti-PD-1/L1 antibody (aPD-1/aPD-L1) and 1-methyl-D,L-tryptophan (1-MT) in melanoma has been well demonstrated, while efficient topical delivery systems are still largely unexplored. Here, a highly drug-concentrated hybrid core-shell microneedle (CSMN) system for co-delivery of checkpoint inhibitors was developed. Based on the specific drug-matrix interaction, the system concentrated aPD-L1 in the tips of microneedles through electrostatic interactions, and increased the amount of 1-MT loaded in CSMN by preventing its premature crystallization using PVA, the material used to prepare CSMN core. The prepared CSMN exhibited high transdermal delivery efficiency and long topical retention time of aPD-L1 for 2 days. Drug-loaded CSMN achieved better anti-tumor efficacy than the intra-tumor injection group at the same dose, which was likely because the former recruited more T lymphocytes to the tumor site. These findings suggested that this CSMN system was a promising local delivery system of both aPD-L1 and 1-MT for melanoma immunotherapy, and its unique core-shell structure could be readily adapted as a modular platform for various diseases, where combination therapy of both biomacromolecular drugs and other small-molecular agents were required. STATEMENT OF SIGNIFICANCE: In the present study, a core-shell microneedle (CSMN) system was constructed to achieve targeted co-delivery of checkpoint inhibitors to melanoma, while preventing significant systemic exposure. To overcome the drawback of insufficient drug loading of microneedles and effectively encapsulate two drugs simultaneously, microneedles were divided into two independent functional areas, a charged shell and a hydrophilic core and encapsulated drugs based on respective drug-matrix interaction. The charged shell prepared by chitosan could concentrate aPD-L1 in the tips of microneedles through electrostatic interactions. The core prepared by PVA successfully increased the amount of 1-MT loaded in microneedles by preventing its premature crystallization. The prepared CSMN exhibited high transdermal delivery efficiency and better anti-tumor efficacy than intra-tumor injection at the same dose.