ao9b01484_si_001.pdf (1.02 MB)
Click Chemistry in the Design and Production of Hybrid Tracers
journal contribution
posted on 2019-07-22, 12:37 authored by Albertus
W. Hensbergen, Danny M. van Willigen, Mick M. Welling, Felicia A. van der Wijk, Clarize M. de Korne, Matthias N. van Oosterom, Margret Schottelius, Hans-Jürgen Wester, Tessa Buckle, Fijs W. B. van LeeuwenHybrid 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.
History
Usage metrics
Categories
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
Licence
Exports
RefWorks
BibTeX
Ref. manager
Endnote
DataCite
NLM
DC