batimastat and Aortic-Aneurysm--Abdominal

Matrix metalloproteinases (MMPs)-mediated extracellular matrix destruction is the major cause of development and progression of abdominal aortic aneurysms. Systemic treatments of MMP inhibitors have shown effectiveness in animal models, but it did not translate to clinical success either because of low doses used or systemic side effects of MMP inhibitors. We propose a targeted nanoparticle (NP)-based delivery of MMP inhibitor at low doses to the abdominal aortic aneurysms site. Such therapy will be an attractive option for preventing expansion of aneurysms in patients without systemic side effects.. Our previous study showed that poly(d,l-lactide) NPs conjugated with an antielastin antibody could be targeted to the site of an aneurysm in a rat model of abdominal aortic aneurysms. 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.. Poly(d,l-lactide) NPs were loaded with BB-94 and conjugated with an elastin antibody. Intravenous injections of elastin antibody-conjugated BB-94-loaded NPs targeted the site of aneurysms and delivered BB-94 in a calcium chloride injury-induced abdominal aortic aneurysms in rats. Such targeted delivery inhibited MMP activity, elastin degradation, calcification, and aneurysmal development in the aorta (269% expansion in control versus 40% elastin antibody-conjugated BB-94-loaded NPs) at a low dose of BB-94. The systemic administration of BB-94 alone at the same dose was ineffective in producing MMP inhibition.. Targeted delivery of MMP inhibitors using NPs may be an attractive strategy to inhibit aneurysmal progression.

Topics: Animals; Aorta, Abdominal; Aortic Aneurysm, Abdominal; Calcium Chloride; Chemistry, Pharmaceutical; Disease Models, Animal; Disease Progression; Drug Carriers; Elastin; Immunoconjugates; Macrophages; Male; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Mice; Nanoparticles; Phenylalanine; Polyesters; Proteolysis; Rats, Sprague-Dawley; RAW 264.7 Cells; Thiophenes; Time Factors; Vascular Calcification

Matrix metalloproteinases (MMPs) are proteolytic enzymes that can degrade the extracellular matrix of the aortic wall and lead to the formation of abdominal aortic aneurysms (AAAs). MMP inhibitors are a class of drugs that were developed to inhibit the activity of these proteolytic enzymes and are currently being studied as a way to control inflammatory diseases and cancer metastases. In this project, BB-94 (also known as batimastat), a specific inhibitor of MMPs, was evaluated for its ability to control aneurysmal growth in an experimental AAA model.. Experimental AAAs were created in a standard rat model by perfusing elastase into an isolated segment of aorta. The rats then were randomized to postoperatively undergo treatment daily with the MMP inhibitor BB-94 or the carrier control solution. Measurements of the aortic diameter were made at the time of initial surgery and at the time of death on postoperative day 7. Aortic tissue was obtained for histologic examination, elastin evaluation, and MAC 1-alpha antibody staining to evaluate the inflammatory response.. The rats that underwent treatment with BB-94 had significantly less aneurysmal dilatation and a 113% increase in aortic size, as compared with the control rats that had a 157% increase (P =.026). Histologic examination of the harvested aortas and grading of the elastin content showed a significantly greater elastin preservation in those rats that were treated with BB-94 as compared with the control rats (P =.036). MAC 1-alpha antibody staining showed an attenuation of the inflammatory response in the group of rats that underwent treatment with BB-94. Morphologic examination also revealed that the control of the inflammatory response correlated with the areas of elastin preservation.. MMP inhibition with BB-94 limited the expansion of AAAs in this rat model. BB-94 appears to work not only as a direct pharmacologic inhibitor of MMPs but also as an interference with the inflammatory response seen in AAAs. Control of the inflammatory response was an unexpected result and may be related to the alterations in feedback mechanisms that are related to extracellular matrix degradation. Because this class of drugs is presently being developed to control the MMP inflammatory response seen with arthritis, these drugs also may ultimately serve as a pharmacologic treatment for patients with AAAs.

Topics: Animals; Antibodies, Monoclonal; Aorta, Abdominal; Aortic Aneurysm, Abdominal; Disease Models, Animal; Male; Metalloendopeptidases; Phenylalanine; Protease Inhibitors; Rats; Rats, Wistar; Thiophenes