Localized doxycycline delivery via polymeric nanoparticles anchored to electrospun PCL microfiber patch for MMP-2 inhibition in abdominal aortic aneurysm

Abstract: Doxycycline (DOXY) is a well-established antibiotic that has recently shown potential in inhibiting matrix metalloproteinase-2 (MMP-2), a key enzyme involved in the progression of abdominal aortic aneurysms (AAA). However, the controlled delivery of DOXY to the aneurysm site, with sustained release and minimal systemic exposure, remains a critical challenge in therapeutic development. To address this, we developed a targeted drug delivery platform based on polymeric nanoparticles (NPs), prepared from water-in-oil-in-water nano-emulsions, encapsulating DOXY and are covalently attached to electrospun ε-poly(caprolactone) (ε-PCL) microfibers. This system was designed to enable local, sustained drug release in the inner wall of aorta while preserving the mechanical properties of the aortic wall. The ε-PCL electrospun microfibers from the patch were first functionalized using oxygen cold plasma treatment, creating free radicals that enabled covalent bonding with chemical groups on the outer layer of DOXY-loaded poly(lactic-co-glycolic acid) (PLGA) NPs. This strategy allowed for robust immobilization of the NPs onto the microfibers surface, forming a composite system capable of localized and controlled drug release over time. Unlike traditional delivery approaches, this method ensures site-specific action of DOXY directly at the aneurysmal tissue, minimizing systemic circulation and reducing off-target toxicity. The platform not only provides a stable drug reservoir but also offers intrinsic biomechanical reinforcement, which is critical in AAA condition. This innovative delivery system represents a significant advance in the localized treatment of vascular disorders. It offers a biocompatible, biodegradable, and precisely targeted therapeutic approach, with potential to reduce the need for surgical intervention and limits the adverse effects associated with systemic drug administration. Highlights: - Novel polymeric Doxycycline loaded PLGA nanoparticles have been developed and result efficacious within hMMP-2 mitigation and collagen degradation in Abdominal Aortic Aneurysm condition. - Doxycycline loaded polymeric nanoparticles were covalently anchored to ε-Poly(caprolactone) electrospun microfibers via cold plasma-induced radical grafting, enabling sustained drug release for over 12 days. - Doxycycline-loaded nanoparticles released from microfibers efficaciously mitigate hMMP-2 in human in vitro models of Abdominal Aortic Aneurysm. - Doxycycline released from drug-coated electrospun ε-Poly(caprolactone) although efficacious does not allows time-control.