Effects of linker variation on the in vitro and in vivo characteristics of an 111In-labeled RGD peptide

Dijkgraaf, I., Liu, S., Kruijtzer, J.A.W., Soede, A.C., Oyen, W.J.G., Liskamp, R.M.J. , Corstens, F.H.M. and Boerman, O.C. (2007) Effects of linker variation on the in vitro and in vivo characteristics of an 111In-labeled RGD peptide. Nuclear Medicine and Biology, 34(1), pp. 29-35. (doi: 10.1016/j.nucmedbio.2006.10.006)

Abstract

Introduction: Due to the selective expression of the α_vβ₃ integrin in tumors, radiolabeled arginine–glycine–aspartic acid (RGD) peptides are attractive candidates for tumor targeting. Minor modifications of these peptides could have a major impact on in vivo characteristics. In this study, we systematically investigated the effects of linker modification between two cyclic RGD sequences and DOTA (1,4,7,10-tetraazadodecane-N,N′,N^ʺ,N^‴-tetraacetic acid) on the in vitro and in vivo characteristics of the tracer. Methods: A dimeric RGD peptide was synthesized and conjugated either directly with DOTA or via different linkers: PEG₄ (polyethylene glycol), glutamic acid or lysine. The RGD peptides were radiolabeled with 111In, and their in vitro and in vivo α_vβ₃-binding characteristics were determined. Results: LogP values varied between −2.82±0.06 and −3.95±0.33. The IC₅₀ values for DOTA-E-[c(RGDfK)]₂, DOTA-PEG₄-E-[c(RGDfK)]₂, DOTA-E-E-[c(RGDfK)]₂ and DOTA-K-E-[c(RGDfK)]₂ were comparable. Two hours after injection, the tumor uptakes of the 111In-labeled compounds were not significantly different. The kidney accumulation of [111In]-DOTA-K-E-[c(RGDfK)]₂ [4.05±0.20% of the injected dose per gram (ID/g)] was significantly higher as compared with that of [111In]-DOTA-E-[c(RGDfK)]₂ (2.63±0.19% ID/g; P<.05) as well as that of [111In]-DOTA-E-E-[c(RGDfK)]₂ (2.16±0.21% ID/g; P<.01). The liver uptake of [111In]-DOTA-E-E-[c(RGDfK)]₂ (2.12±0.09% ID/g) was significantly higher as compared with that of [111In]-DOTA-E-[c(RGDfK)]₂ (1.64±0.1% ID/g; P<.05) as well as that of [111In]-DOTA-K-E-[c(RGDfK)]₂ (1.52±0.04% ID/g;P<.01). Conclusions: Linker variation did not affect affinity for α_vβ₃ and tumor uptake. Insertion of lysine caused enhanced kidney retention; that of glutamic acid also resulted in enhanced retention in the kidneys. PEG4 appeared to be the most suitable linker as compared with glutamic acid and lysine because it has the highest tumor-to-blood ratio and the lowest uptake in the kidney and liver.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Liskamp, Professor Robert
• Authors: Dijkgraaf, I., Liu, S., Kruijtzer, J.A.W., Soede, A.C., Oyen, W.J.G., Liskamp, R.M.J., Corstens, F.H.M., and Boerman, O.C.
• College/School: College of Science and Engineering > School of Chemistry
• Journal Name: Nuclear Medicine and Biology
• Publisher: Elsevier Inc.
• ISSN: 0969-8051
• ISSN (Online): 1872-9614