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

Mandeep Kaur Marwah; Pavanjeeth Balakrishnan; Sarah Junaid; Shakil Ahmad; Hala Shokr; Manoj Upadhya; Lissette Sanchez-Aranguren

doi:10.1016/j.ijpharm.2025.126535

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

Mandeep Kaur Marwah^*, Pavanjeeth Balakrishnan, Sarah Junaid, Shakil Ahmad, Hala Shokr, Manoj Upadhya, Lissette Sanchez-Aranguren

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	126535
Number of pages	12
Journal	International Journal of Pharmaceutics
Volume	690
Early online date	24 Dec 2025
DOIs	https://doi.org/10.1016/j.ijpharm.2025.126535
Publication status	E-pub ahead of print - 24 Dec 2025

Bibliographical note

Keywords

Drug delivery
Nanoparticles
Controlled drug release
Hydrogen sulphide donors

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10.1016/j.ijpharm.2025.126535Licence: CC BY 4.0

Mandeep Kaur Marwah et al_PLGA nanoparticle-integrated microneedles for controlled transdermal delivery of ADT-OH to ameliorate endothelial dysfunction in vitro
Crown Copyright © 2025 Published by Elsevier B.V. This is an open access article under the CC BY license (https://creativecommons.org/licenses/by/4.0/).
Final published version, 6.09 MBLicence: CC BY 4.0

Cite this

Marwah, M. K., Balakrishnan, P., Junaid, S., Ahmad, S., Shokr, H., Upadhya, M., & Sanchez-Aranguren, L. (2026). PLGA nanoparticle-integrated microneedles for controlled transdermal delivery of ADT-OH to ameliorate endothelial dysfunction in vitro. International Journal of Pharmaceutics, 690, Article 126535. Advance online publication. https://doi.org/10.1016/j.ijpharm.2025.126535

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AU - Marwah, Mandeep Kaur

AU - Balakrishnan, Pavanjeeth

AU - Junaid, Sarah

AU - Ahmad, Shakil

AU - Shokr, Hala

AU - Upadhya, Manoj

AU - Sanchez-Aranguren, Lissette

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N2 - 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 rapidclearance 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 transdermalrelease 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 HUVECtube 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.

AB - 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 rapidclearance 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 transdermalrelease 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 HUVECtube 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.

KW - Drug delivery

KW - Nanoparticles

KW - Controlled drug release

KW - Hydrogen sulphide donors

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DO - 10.1016/j.ijpharm.2025.126535

M3 - Article

SN - 0378-5173

VL - 690

JO - International Journal of Pharmaceutics

JF - International Journal of Pharmaceutics

M1 - 126535

ER -

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

Abstract

Bibliographical note

Keywords

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