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Assessment of 177Lu-labeled carboxyl-terminated polyamidoamine (PAMAM) dendrimer-RGD peptide conjugate
Journal of Peptide Science ( IF 1.8 ) Pub Date : 2021-08-30 , DOI: 10.1002/psc.3366
Kusum Vats 1, 2 , Rohit Sharma 1, 2 , Amit Kumar Sharma 1, 2 , Haladhar D Sarma 3 , Drishty Satpati 1, 2
Affiliation  

Structurally unique polyamidoamine (PAMAM) dendrimers implanted with targeting biological moiety along with complexed radiometal constitute a favorable nano-system for diagnosis and therapy of targeted tumor sites. In the present study, carboxyl functionalities of PAMAM- generation 4 dendrimer (PAMAM-G4-COOH) were conjugated with ε-amino group of lysine of cRGDfK peptide to impart integrin αvβ3 targeting capability. Reaction of p-NH2-Bn-DOTA with PAMAM was accomplished via acid-amine coupling using EDC/NHS for 177Lu-complexation. 177Lu-labeled nano-system, 177Lu-PAMAM-DOTA-cRGDfK demonstrated receptor-mediated uptake in murine melanoma B16F10 cells during in vitro cell uptake studies. In vivo biodistribution studies demonstrated low tumor uptake and retention of 177Lu-PAMAM-DOTA-cRGDfK which may be attributed to rapid blood clearance. However, fast clearance from non-target organs resulted in higher target to background ratio. Tumor uptake of targeted nano-system, 177Lu-PAMAM-DOTA-cRGDfK was observed to be significantly (p < 0.05) higher in comparison to 177Lu-PAMAM-DOTA without the targeting peptide. Inhibition studies with unlabeled cRGDfK resulted in 60% reduction in tumor uptake of 177Lu-PAMAM-DOTA-cRGDfK, indicating specificity of the developed nano-system towards integrin αvβ3 receptors.

中文翻译:

177Lu 标记的羧基末端聚酰胺胺 (PAMAM) 树枝状大分子-RGD 肽缀合物的评估

结构独特的聚酰胺胺 (PAMAM) 树枝状大分子植入了靶向生物部分以及复合的放射性金属,构成了用于诊断和治疗靶向肿瘤部位的有利纳米系统。在本研究中,PAMAM-第 4 代树枝状大分子 (PAMAM-G4-COOH) 的羧基官能团与 cRGDfK 肽的赖氨酸的 ε-氨基结合,以赋予整合素 α v β 3靶向能力。p-NH 2 -Bn-DOTA 与 PAMAM 的反应是通过酸-胺偶联使用 EDC/NHS 进行177 Lu-络合来完成的。177 Lu 标记的纳米系统,177Lu-PAMAM-DOTA-cRGDfK 在体外细胞摄取研究中证明了受体介导的小鼠黑色素瘤 B16F10 细胞摄取。体内生物分布研究表明177 Lu-PAMAM-DOTA-cRGDfK 的低肿瘤摄取和保留可能归因于快速的血液清除。然而,从非靶器官的快速清除导致更高的靶背景比。与没有靶向肽的177 Lu-PAMAM-DOTA 相比,观察到靶向纳米系统177 Lu-PAMAM-DOTA-cRGDfK 的肿瘤摄取显着(p  < 0.05)更高。使用未标记的 cRGDfK 进行的抑制研究导致177的肿瘤摄取减少了 60%Lu-PAMAM-DOTA-cRGDfK,表明开发的纳米系统对整合素 α v β 3受体的特异性。
更新日期:2021-08-30
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