Department of Radiopharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
Bioorg Chem. 2020 May;98:103731. doi: 10.1016/j.bioorg.2020.103731. Epub 2020 Mar 6.
In cardiac ischemic disorder, pyroglutamate helix B surface peptide (pHBSP) which derived from erythropoietin causes to increase cell stability. To improve the serum stability of pHBSP, two lipophilic amino acids Arg, Ala were replaced with Fmoc-(Dabcyle)-Lys-OH and Fmoc-Phe-OH during the peptide synthesis. This peptide was subsequently conjugated to PEGylated dendrimer-G and labeled with TcO to detect cardiac ischemic region. Radiochemical purity (RCP) of Tc-PEGylated dendrimer-G-(Dabcyle-Lys,Phe)-pHBSP was evaluated by ITLC method. In addition, the radiopeptide was investigated for stability in human serum and binding affinity to hypoxic cells in myocardium H9c2 cell lines. Biodistribution and SPECT/CT scintigraphy were assessed in cardiac ischemic rats. Radiochemical yield indicated that the anionic dendrimer has a very high potential to complex formation with TcO (RCP > 94%) which was stable in human serum with RCP 89% up to 6 h. The binding of Tc- nanoconjugate to hypoxic cells was significantly more than normoxic cells (3-fold higher compared to normoxic cells at 1 h). In biodistribution studies, erythropoietin receptor-Beta common receptor (EPO-BcR)-positive uptake in the cardiac ischemic region was 3.62 ± 0.44% ID/g 30 min post injection. SPECT imaging showed a prominent uptake of Tc-nanoconjugate in EPO-BcR expressing ischemic heart.
在心脏缺血性疾病中，来源于促红细胞生成素的焦谷氨酸螺旋 B 表面肽（pHBSP）可导致细胞稳定性增加。为了提高 pHBSP 的血清稳定性，在肽合成过程中，用 Fmoc-（Dabcyl）-Lys-OH 和 Fmoc-Phe-OH 替换了两个疏水性氨基酸 Arg 和 Ala。随后，该肽与聚乙二醇化树枝状大分子-G 缀合，并与 TcO 标记以检测心脏缺血区域。通过 ITLC 法评估 Tc-PEG 化树枝状大分子-G-（Dabcyl-Lys，Phe）-pHBSP 的放射化学纯度（RCP）。此外，还研究了放射性肽在人血清中的稳定性以及与心肌 H9c2 细胞系缺氧细胞的结合亲和力。在心脏缺血大鼠中进行了生物分布和 SPECT/CT 闪烁照相研究。放射化学产率表明，带负电荷的树枝状大分子与 TcO 具有很高的形成复合物的潜力（RCP＞94%），在人血清中稳定，6 h 时 RCP 为 89%。Tc-纳米复合物与缺氧细胞的结合明显高于正常氧细胞（与正常氧细胞相比，1 h 时高 3 倍）。在生物分布研究中，心脏缺血区的促红细胞生成素受体-β共受体（EPO-BcR）阳性摄取为 3.62±0.44% ID/g，注射后 30 min。SPECT 成像显示 EPO-BcR 表达的缺血性心脏中 Tc-纳米复合物摄取明显。
