Nanoparticles for localized delivery of hyaluronan oligomers (HA-o) towards regenerative repair of elastic matrix

摘要

Abdominal aortic aneurysms (AAAs) are rupture-prone progressive dilations of the infrarenal aorta due to a loss of elastic matrix that lead to weakening of the aortic wall. Therapies to coax biomimetic regenerative repair of the elastic matrix by resident, diseased vascular cells may thus be useful to slow, arrest, or regress AAA growth. Hyaluronan oligomers (HA-o) have been shown to induce elastic matrix synthesis by healthy and aneurysmal rat aortic smooth muscle cells (SMCs) in vitro but only via exogenous dosing, which potentially has side effects and limitations to in vivo delivery towards therapy. In this paper, we describe the development of HA-o loaded poly(lactide-co-glycolide) (PLGA) nanoparticles (NPs) for targeted, controlled, and sustained delivery of HA-o towards the elastogenic induction of aneurysmal rat aortic SMCs. These NPs were able to deliver HA-o over an extended period (>30 days) at previously determined elastogenic doses (0.2 – 20 μg/mL). HA-o released from the NPs led to dose dependent increases in elastic matrix synthesis, and the recruitment and activity of lysyl oxidase (LOX), the enzyme which crosslinks elastin precursor molecules into mature fibers/matrix. Therefore, we were able to successfully develop a nanoparticle based system for controlled and sustained HA-o delivery for the in vitro elastogenic induction of aneurysmal rat aortic smooth muscle cells (EaRASMCs).