From the Department of Nuclear Medicine, Molecular Imaging and Therapeutic Medicine Research Center, Cyclotron Research Center, Institute for Medical Sciences, and Biomedical Research Institute, Chonbuk National University Medical School and Hospital, 634-18 GeumAm-dong Duckjin-gu Jeonju-si, Jeollabuk-do 561-803, South Korea (H.H., J.K., P.S.O., T.K.L., K.S.N., H.S.J., S.T.L., M.H.S., H.J.J.); and Department of Biomedical Engineering, Chonnam National University, Yeosu, South Korea (C.M.L.).
Radiology. 2014 Oct;273(1):160-7. doi: 10.1148/radiol.14132942. Epub 2014 Jun 12.
To determine whether chitosan hydrogel nanoparticles loaded with vascular endothelial growth factor (VEGF) peptides (81-91 fragments) capable of targeting the ischemic myocardium enhance angiogenesis and promote therapeutic effects and whether radionuclide image-guided dosage control is feasible.
Experimental procedures and protocols were approved by the Institutional Animal Care and Use Committee. Rats (n = 32, eight per group) were subjected to myocardial ischemia (control group) and received chitosan hydrogel nanoparticles with VEGF165 proteins (chitosan VEGF) or VEGF81-91 peptides (chitosan peptides) via apical puncture. Ischemic hearts receiving chitosan without angiogenic factors served as the chitosan control. Myocardial perfusion was examined 7 days after surgery by using technetium 99m ((99m)Tc) tetrofosmin (37 MBq) autoradiography, and changes in vascular density with immunohistochemical staining were reviewed. Kruskal-Wallis test and Bonferroni corrected Mann-Whitney U test were used for multiple comparisons. Wilcoxon signed rank test was used to compare myocardial retention of (99m)Tc chitosan.
Thirty minutes of myocardial ischemia resulted in perfusion defects (median, 54%; interquartile range [IQR], 41%-62%). Chitosan VEGF decreased perfusion defect extent (median, 68%; IQR, 63%-73%; P = .006 vs control) and increased vascular density (median, 81 vessels per high-power field; IQR, 72-100; P = .009 vs control). Administration of chitosan peptides reduced the degree of perfusion defects (median, 66%; IQR, 62%-73%; P = .006 vs control) and increased vascular density (median, 82 vessels; IQR, 78-92; P = .006 vs control). The effects of chitosan peptides on perfusion and vascular density were comparable to those seen with chitosan VEGF proteins (P = .713 and P = .833, respectively). Chitosan radiolabeled with (99m)Tc was administered twice at reperfusion with a 1-hour interval to determine whether image-guided dosage control is feasible. The hearts initially retained 4.6% (IQR, 4.1%-5.0%) of (99m)Tc chitosan administered and 9.2% (IQR, 6.6%-12.7%; P = .068) with subsequent injection.
VEGF peptides have angiogenic potential and resulted in therapeutic effectiveness. Adjunct use of single photon emission computed tomography was also demonstrated for individualized treatment of myocardial ischemia by further tailoring the therapeutic dosing. Online supplemental material is available for this article.
确定负载血管内皮生长因子（VEGF）肽（81-91 片段）的壳聚糖水凝胶纳米颗粒（能够靶向缺血心肌）是否能增强血管生成并促进治疗效果，以及放射性核素图像引导剂量控制是否可行。
实验程序和方案得到了机构动物护理和使用委员会的批准。将大鼠（n=32，每组 8 只）进行心肌缺血（对照组）处理，并通过心尖穿刺给予壳聚糖水凝胶与 VEGF165 蛋白（壳聚糖 VEGF）或 VEGF81-91 肽（壳聚糖肽）。接受无血管生成因子的壳聚糖的缺血心脏作为壳聚糖对照。手术后 7 天通过锝 99m（99m）Tc 四氮戊二酸（37MBq）放射自显影术检查心肌灌注情况，并通过免疫组织化学染色观察血管密度变化。使用 Kruskal-Wallis 检验和 Bonferroni 校正的 Mann-Whitney U 检验进行多重比较。Wilcoxon 符号秩检验用于比较（99m）Tc 壳聚糖的心肌保留情况。
30 分钟的心肌缺血导致灌注缺陷（中位数，54%；四分位距 [IQR]，41%-62%）。壳聚糖 VEGF 降低了灌注缺陷程度（中位数，68%；IQR，63%-73%；P=0.006 比对照组）并增加了血管密度（中位数，81 个/高倍视野；IQR，72-100；P=0.009 比对照组）。给予壳聚糖肽可降低灌注缺陷程度（中位数，66%；IQR，62%-73%；P=0.006 比对照组）并增加血管密度（中位数，82 个；IQR，78-92；P=0.006 比对照组）。壳聚糖肽对灌注和血管密度的影响与壳聚糖 VEGF 蛋白相似（P=0.713 和 P=0.833）。用（99m）Tc 标记的壳聚糖在再灌注时两次给药，间隔 1 小时，以确定图像引导剂量控制是否可行。心脏最初保留了 4.6%（IQR，4.1%-5.0%）的（99m）Tc 壳聚糖，随后注射时保留了 9.2%（IQR，6.6%-12.7%；P=0.068）。
VEGF 肽具有血管生成潜力，并产生了治疗效果。单光子发射计算机断层扫描的附加使用也通过进一步调整治疗剂量，为心肌缺血的个体化治疗提供了证据。本文提供了在线补充材料。
