Nosoudi Nasim, Nahar-Gohad Pranjal, Sinha Aditi, Chowdhury Aniqa, Gerard Patrick, Carsten Christopher G, Gray Bruce H, Vyavahare Naren R
From the Department of Bioengineering, Clemson University, SC (N.N., P.N.-G., A.S., A.C., P.G., N.R.V.); Department of Biomedical Engineering, Edwards Lifesciences Center for Advanced Cardiovascular Technology, University of California, Irvine (A.S.); and Division of Vascular Surgery, Greenville Health System, SC (C.G.C., B.H.G.).
Circ Res. 2015 Nov 6;117(11):e80-9. doi: 10.1161/CIRCRESAHA.115.307207. Epub 2015 Oct 6.
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.
基质金属蛋白酶（MMPs）介导的细胞外基质破坏是腹主动脉瘤发生和发展的主要原因。MMP抑制剂的全身治疗在动物模型中已显示出有效性，但由于使用剂量低或MMP抑制剂的全身副作用，并未转化为临床成功。我们提出以低剂量将MMP抑制剂靶向递送至腹主动脉瘤部位的纳米颗粒（NP）。这种治疗将是预防患者动脉瘤扩张且无全身副作用的有吸引力的选择。
我们之前的研究表明，与抗弹性蛋白抗体偶联的聚（d，l-丙交酯）NP可靶向大鼠腹主动脉瘤模型中的动脉瘤部位。在本报告的研究中，我们测试了这种靶向NP是否能将MMP抑制剂batimastat（BB-94）递送至动脉瘤部位并预防动脉瘤生长。
将BB-94负载于聚（d，l-丙交酯）NP并与弹性蛋白抗体偶联。静脉注射与弹性蛋白抗体偶联的负载BB-94的NP可靶向大鼠氯化钙损伤诱导的腹主动脉瘤部位，并在低剂量BB-94时递送BB-94。这种靶向递送抑制了主动脉中的MMP活性、弹性蛋白降解、钙化和动脉瘤发展（对照组扩张269%，而与弹性蛋白抗体偶联的负载BB-94的NP组为40%）。相同剂量单独全身给予BB-94在产生MMP抑制方面无效。
使用NP靶向递送MMP抑制剂可能是抑制动脉瘤进展的有吸引力的策略。
