Assessment of 177Lu-labeled carboxyl-terminated polyamidoamine (PAMAM) dendrimer-RGD peptide conjugate,Journal of Peptide Science

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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 α_vβ₃ 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 α_vβ₃ 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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