Click Chemistry in the Design and Production of Hybrid
Tracers
Version 4 2019-08-06, 19:24
Version 3 2019-08-05, 18:08
Version 2 2019-08-05, 14:34
Version 1 2019-07-22, 12:37
Posted on 2019-08-06 - 19:24
Hybrid tracers containing both fluorescent
and radioactive imaging
labels have demonstrated clinical potential during sentinel lymph
node procedures. To combine these two labels on a single targeting
vector that allows tumor-targeted imaging, end-labeling strategies
are often applied. For αvβ3-integrin-targeting hybrid tracers, providing an excellent model
for evaluating tracer development strategies, end-labeling-based synthesis
provides a rather cumbersome synthesis strategy. Hence, the aim of
this study was to investigate the use of heterobifunctional cyanine
dyes in a click-chemistry-based synthesis strategy for RGD-based hybrid
tracers. The triazole-based hybrid tracers DTPA.DBCO.N3(SO3)-Cy5-c[RGDyK] and DTPA.BCN.N3(SO3)-Cy5-c[RGDyK] were obtained in fewer steps than DTPA-Lys(Cy5(SO3)methyl)-Cys-c[RGDyK] and had partition
coefficients of log P(o/w) = −2.55
± 0.10, −1.45 ± 0.03, and −2.67 ± 0.12,
respectively. Both tracers were chemically stable, and the brightnesses
of DTPA.DBCO.N3(SO3)-Cy5-c[RGDyK] and DTPA.BCN.N3(SO3)-Cy5-c[RGDyK] were, respectively, 23 × 103 and 40 × 103 M–1 cm–1; lower than that of the reference tracer DTPA-Lys(Cy5(SO3)methyl)-Cys-c[RGDyK] (50 × 103 M–1 cm–1). Assessment of serum protein binding revealed no statistically significant
difference (44 ± 2 and 40 ± 2% bound for DTPA.DBCO.N3(SO3)-Cy5-c[RGDyK] and DTPA.BCN.N3(SO3)-Cy5-c[RGDyK], respectively; 36 ± 5% bound for DTPA-Lys(Cy5(SO3)methyl)-Cys-c[RGDyK]; p > 0.05). DTPA.DBCO.N3(SO3)-Cy5-c[RGDyK] (KD = 17.5 ± 6.0) had a statistically significantly
higher affinity than the reference compound DTPA-Lys(Cy5(SO3)methyl)-Cys-c[RGDyK] (KD = 30.3 ± 5.7; p <
0.0001), but DTPA.BCN.N3(SO3)-Cy5-c[RGDyK] had
a statistically significantly lower affinity (KD = 76.5 ± 18.3 nM; p < 0.0001).
Both [111In]DTPA.DBCO.N3(SO3)-Cy5-c[RGDyK] and [111In]DTPA.BCN.N3(SO3)-Cy5-c[RGDyK] enabled in vivo
visualization of the 4T1 tumor via fluorescence and single-photon
emission computed tomography (SPECT) imaging. Biodistribution data
(% ID/g) revealed a significant increase in nonspecific uptake in
the kidney, liver, and muscle for both [111In]DTPA.DBCO.N3(SO3)-Cy5-c[RGDyK] and [111In]DTPA.BCN.N3(SO3)-Cy5-c[RGDyK]. As a result of the higher background activity, the tumor-to-background
ratio of the click-labeled RGD analogues was twofold lower compared
to the end-labeled reference compound. The use of click chemistry labeling
did not yield a pronounced negative effect on serum protein binding,
in vitro stability, and receptor affinity; and tumors could still
be visualized using SPECT and fluorescence imaging. However, quantitative
in vivo biodistribution data suggest that the triazole and strained
cyclooctyne moieties associated with this type of click chemistry
negatively influence the pharmacokinetics of RGD peptides. Nevertheless,
the design might still hold promise for other targets/targeting moieties.
CITE THIS COLLECTION
DataCite
3 Biotech
3D Printing in Medicine
3D Research
3D-Printed Materials and Systems
4OR
AAPG Bulletin
AAPS Open
AAPS PharmSciTech
Abhandlungen aus dem Mathematischen Seminar der Universität Hamburg
ABI Technik (German)
Academic Medicine
Academic Pediatrics
Academic Psychiatry
Academic Questions
Academy of Management Discoveries
Academy of Management Journal
Academy of Management Learning and Education
Academy of Management Perspectives
Academy of Management Proceedings
Academy of Management Review
Hensbergen, Albertus
W.; van Willigen, Danny M.; Welling, Mick M.; van der Wijk, Felicia A.; de Korne, Clarize M.; van Oosterom, Matthias N.; et al. (2019). Click Chemistry in the Design and Production of Hybrid
Tracers. ACS Publications. Collection. https://doi.org/10.1021/acsomega.9b01484
or
Select your citation style and then place your mouse over the citation text to select it.
SHARE
Usage metrics
Read the peer-reviewed publication
AUTHORS (10)
AH
Albertus
W. Hensbergen
Dv
Danny M. van Willigen
MW
Mick M. Welling
Fv
Felicia A. van der Wijk
Cd
Clarize M. de Korne
Mv
Matthias N. van Oosterom
MS
Margret Schottelius
HW
Hans-Jürgen Wester
TB
Tessa Buckle
FW
Fijs W. B. van Leeuwen
KEYWORDS
4 T 1 tumorDTPA.BCN.N 3heterobifunctional cyanine dyesserum protein bindingvivo biodistribution datatracer development strategiesend-labeled reference compounduse of click chemistryK DHybrid Tracers Hybrid tracersclick-labeled RGD analoguesIDα v β 3click-chemistry-based synthesis strategyCy5-cSPECTsentinel lymph node proceduresDTPA.DBCO.N 3tracers DTPA.DBCO.N 3