Newton Emily R, Gillis David C, Sun Kui, Dandurand Brooke R, Siletzky Robin, Biswas Suvendu, Karver Mark R, Tsihlis Nick D, Stupp Samuel I, Kibbe Melina R
Department of Surgery, Center for Nanotechnology in Drug Delivery, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Simpson Querrey Institute, Northwestern University, Chicago, IL 60611, USA.
Adv Nanobiomed Res. 2021 Jul;1(7). doi: 10.1002/anbr.202000093. Epub 2021 Apr 3.
To test the hypothesis that nitric oxide-bearing collagen-targeted nanofibers will target vascular injury and inhibit neointimal hyperplasia in an atherosclerotic rat model.
Western blot confirms apolipoprotein E (ApoE) knockout (-/-) status. Serum cholesterol increases three-fold in Sprague Dawley (SD) ApoE-/- . wt SD rats (291.7±22.3 . 105.0±3.6 mg/dL, p<0.05). Oxidative stress markers are elevated in SD ApoE-/- . wt SD strains (p=0.002). Oil Red O staining shows lipid-rich lesions in SD ApoE-/- aortas. Transmission electron microscopy shows co-assembled peptide amphiphiles (PA) form nanofibers. Fluorescence microscopy shows targeting of collagen-binding peptide (CBP)-S-nitrosyl(SNO)-PA nanofiber to arteries 20 minutes after injury, while uninjured carotid and non-targeted SNO-PA nanofibers show minimal localization (3444.8±282.0, 11.0±2.3, and 451.4±93.6 arbitrary units, respectively, p<0.05). Two weeks after injury and injection, CBP-SNO-PA nanofibers inhibit neointimal hyperplasia by 67% . injury alone (p<0.0001). Intima/media (I/M) ratios are 0.3, 1.0, and 0.9 for CBP-SNO-PA nanofiber, scrambled SNO-PA nanofiber, and injury alone, respectively (p<0.0001). Results are durable out to 3 months (I/M 0.6 . 1.4 for CBP-SNO-PA . injury alone, p<0.0001).
Targeted drug-eluting nanofibers localize to vascular injury, decrease neointimal hyperplasia after 2 weeks, and are durable out to 3 months in an atherosclerotic rat model.
验证携带一氧化氮的胶原蛋白靶向纳米纤维在动脉粥样硬化大鼠模型中能够靶向血管损伤并抑制内膜增生的假说。
蛋白质印迹法证实载脂蛋白E（ApoE）基因敲除（-/-）状态。在Sprague Dawley（SD）ApoE-/-大鼠中，血清胆固醇增加了两倍。野生型SD大鼠血清胆固醇水平为（291.7±22.3）mg/dL，而ApoE-/-大鼠为（105.0±3.6）mg/dL，p<0.05。氧化应激标志物在SD ApoE-/-大鼠中升高。野生型SD大鼠品系中（p = 0.002）。油红O染色显示SD ApoE-/-大鼠主动脉中有富含脂质的病变。透射电子显微镜显示共组装的肽两亲分子（PA）形成纳米纤维。荧光显微镜显示，损伤后20分钟，胶原结合肽（CBP）-S-亚硝基硫醇（SNO）-PA纳米纤维靶向动脉，而未损伤的颈动脉和非靶向的SNO-PA纳米纤维显示出最小的定位（分别为3444.8±282.0、11.0±2.3和451.4±93.6任意单位，p<0.05）。损伤和注射后两周，CBP-SNO-PA纳米纤维抑制内膜增生67%，单独损伤组为（p<0.0001）。CBP-SNO-PA纳米纤维、随机SNO-PA纳米纤维和单独损伤组的内膜/中膜（I/M）比值分别为0.3、1.0和0.9（p<0.0001）。结果在3个月内持续存在（CBP-SNO-PA纳米纤维组与单独损伤组的I/M比值分别为0.6和1.4，p<0.0001）。
在动脉粥样硬化大鼠模型中，靶向药物洗脱纳米纤维定位于血管损伤部位，在2周后减少内膜增生，并在3个月内持续有效。
