The degradation of elastic matrix in the infrarenal aortic wall is a critical parameter underlying the formation and progression of abdominal aortic aneurysms (AAAs). It is mediated by the chronic overexpression of matrix metalloproteases (MMPs) -2 and -9, leading to a progressive loss of elasticity and weakening of the aortic wall. Delivery of therapeutic agents to inhibit MMPs, while concurrently coaxing cell-based regenerative repair of the elastic matrix represents a potential strategy for slowing or arresting AAA growth. Our prior studies have demonstrated elastogenic induction of healthy and aneurysmal aortic smooth muscle cells (SMCs) and inhibition of MMPs, following exogenous delivery of elastogenic factors such as TGF-β1, as well as MMP-inhibitors such as doxycycline (DOX) in two-dimensional (2-D) culture. Based on these findings, and others that demonstrated elastogenic benefits of nanoparticulate delivery of these agents in 2-D culture, we have developed poly(lactide-co-glycolide) nanoparticles for localized, controlled and sustained delivery of DOX and TGF-β1 to human aortic SMCs (HASMCs) within a three-dimensional (3-D) gels of type-I collagen gel, which closely evoke the arterial tissue microenvironment. DOX and TGF-β1 released from these NPs influenced elastogenic outcomes positively within the collagen constructs over 21 days of culture, which were comparable to that induced by exogenous supplementation of DOX and TGF-β1 within the culture medium. However, this was accomplished at doses ∼20-fold lower than the exogenous dosages of the agents, illustrating that their localized, controlled, and sustained delivery from NPs embedded within a 3-D scaffold is an efficient strategy for directed elastogenesis.
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