Prevention of Abdominal Aortic Aneurysm Progression by Targeted Inhibition of Matrix Metalloproteinase Activity with Batimastat-Loaded Nanoparticles
Rationale: Matrix metalloproteinases (MMPs)-mediated extracellular matrix destruction is the major cause of development and progression of abdominal aortic aneurysms (AAA). Systemic treatments of MMP inhibitors have shown effectiveness in animal models but it did not translate to clinical success either due low doses used or systemic side-effects of MMP inhibitors. We propose a targeted nanoparticle based delivery of MMP inhibitor at very low doses to the AAA site. Such therapy will be an attractive option for preventing expansion of aneurysms in patients without systemic side effects.
Objective: Our previous study showed that poly D, L-lactide (PLA) nanoparticles (NPs) conjugated with an anti-elastin antibody could be targeted to the site of an aneurysm in a rat model of AAA. In the study reported here, we tested whether such targeted NPs could deliver the MMP inhibitor batimastat (BB-94) to the site of an aneurysm and prevent aneurysmal growth.
Methods and Results: PLA NPs were loaded with BB-94 and conjugated with an elastin antibody. Intravenous injections of elastin antibody-conjugated BB-94-loaded NPs (EL-NP-BB94) targeted the site of aneurysms and delivered BB-94 in a calcium chloride injury-induced AAA in rats. Such targeted delivery inhibited MMP activity, elastin degradation, calcification, and aneurysmal development in the aorta (269% expansion in control vs. 40% EL-NP-BB94) at a low dose of BB-94. The systemic administration of BB-94 alone at the same dose was ineffective in producing MMP inhibition.
Conclusions: Targeted delivery of MMP inhibitors using NPs may be an attractive strategy to inhibit aneurysmal progression.
- cardiovascular diseases
- targeted therapy
- MMP inhibitor
- vascular remodeling
- drug delivery system
- abdominal aortic aneurysm
- Received July 13, 2015.
- Revision received September 30, 2015.
- Accepted October 5, 2015.