PLGA nanoparticle-integrated microneedles for controlled transdermal delivery of ADT-OH to ameliorate endothelial dysfunction in vitro

Abstract

Endothelial dysfunction, a central feature of vascular diseases such as diabetes and atherosclerosis, is associated with oxidative stress and inflammation. Hydrogen sulphide-donors such as ADT-OH provide vascular protection but suffer from rapid clearance and poor bioavailability. To address this, we developed a dual-polymer delivery system that integrates biodegradable poly(lactic-co-glycolic acid) (PLGA) nanoparticles within poly(vinyl alcohol) microneedles to achieve sustained transdermal release of ADT-OH.   Microneedle arrays were fabricated from poly(vinyl alcohol) and trehalose, incorporating free ADT-OH or ADT-OH–loaded PLGA nanoparticles. Mechanical strength and insertion capacity of polymeric microneedles were characterised, followed by ex-vivo Franz diffusion studies in murine skin. The polymer system was further evaluated for its ability to preserve drug activity in a HUVEC model of endothelial dysfunction. Nanoparticles were successfully prepared and characterised by STEM imaging and HPLC-UV, confirming efficient encapsulation. Incorporation into dissolving microneedles did not compromise their structural integrity or penetration efficiency. Compared with unencapsulated drug, nanoparticle-loaded ADT-OH observed sustained release (56.3 ± 7.4% vs. 40.2 ± 7.2% in 24h). In endothelial dysfunction models, TNF-α stimulation elevated IL-6 secretion (80.63 ± 9.90pg/mL), which was suppressed by permeated ADT-OH (48.17 ± 9.64pg/mL, p<0.0001). Treatment significantly reduced intracellular ROS and preserved mitochondrial function. Permeated ADT-OH retained pro-angiogenic activity, significantly enhancing HUVEC tube formation (p≤0.01). This study demonstrates that integrating poly(vinyl alcohol) microneedles with PLGA nanoparticles provides a polymer-based platform for minimally invasive, sustained delivery of hydrogen sulphide-donors. The system preserved anti-inflammatory, antioxidant, and pro-angiogenic activities of ADT-OH, underscoring its potential to restore endothelial function.