Fast clearing RGDa??based neara??infrared fluorescent probes for in vivo tumor diagnosis

摘要

A fast clearing hydrophilic neara??infrared (NIR) dye ICGa??Dera??02 was used to constitute tumor targeting contrast agents. Cell adhesion molecule integrin ?±v?23 served as the target receptor because of its unique expression on almost all sprouting tumor vasculatures. The purpose of this study was to synthesize and compare the properties of integrin ?±v?23a??targeted, fast clearing NIR probes both in vitro and in vivo for tumor diagnosis. ICGa??Dera??02 was covalently conjugated to three kinds of RGD peptide including linear, monoeric cyclic and dimeric RGD to form three RGDa??based NIR probes. The integrin receptor specificities of these probes were evaluated in vitro by confocal microscopy. The dynamic bioa??distribution and elimination ratse were in vivo reala??time monitored by a neara??infrared imaging system in normal mice. Further, the in vivo tumor targeting abilities of the RGDa??based NIR probes were compared in ?±v?23a??positive MDAa??MBa??231, U87MG and ?±v?23a??negtive MCFa??7 xenograft mice models. Three RGDa??based NIR probes were successfully synthesized with good optical properties. In vitro cellular experiments indicated that the probes have a clear binding affinity to ?±???23a??positive tumor cells, with a cyclic dimeric RGD probe owing the highest integrin affinity. Dynamic bioa??distributions of these probes showed a rapid clearing rate through the renal pathway. In vivo tumor targeting ability of the RGDa??based porbes was demonstrated on MDAa??MBa??231 and U87MG tumor models. As expected, the c(RGDyK)2a??ICGa??Dera??02 probe displayed the highest tumora??toa??normal tissue contrast. The in vitro and in vivo block experiments confirmed the receptor binding specificity of the probes. The hydrophilic dyea??labeled NIR probes exhibited a fast clearing rate and deep tissue penetration capability. Further, the ?±???23 receptor affinity of the three RGDa??based NIR probes followed the order of dimer cyclic monomer cyclic linear. The results demonstrate potent fast clearing probes for in vivo early tumor diagnosis. Copyright ?? 2012 John Wiley & Sons, Ltd.