RESUMO
C-X-C chemokine receptor type 4 (CXCR4) constitutes a promising target for tumor diagnosis and therapy. Herein, we evaluate a new 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-conjugated CXCR4 antagonist derived from LY2510924, FRM001, and its metal complexes as CXCR4-targeting probes. FRM001 was synthesized by modifying the C-terminus of LY2510924 with maleimido-mono-amide-DOTA via a cysteine linker. FRM001 exhibited CXCR4-specific binding with an affinity similar to that of the parental LY2510924. The binding affinity of FRM001 remained unchanged after complexation with Ga, Lu, and Y. The internalization of 67Ga-FRM001 into the cells was hardly observed. In mice biodistribution studies, 67Ga-FRM001 exhibited high accumulation in the tumor and the liver with rapid elimination rates from the blood. The hepatic accumulation of 67Ga-FRM001 was preferentially and significantly reduced by co-injecting a CXCR4 antagonist, AMD3100. The C-terminal-modified LY2510924 would constitute a versatile scaffold to develop CXCR4-targeting probes or therapeutics for tumor imaging or therapy.
Assuntos
Radioisótopos de Gálio/metabolismo , Compostos Heterocíclicos/metabolismo , Neoplasias/metabolismo , Peptídeos Cíclicos/metabolismo , Peptídeos/metabolismo , Receptores CXCR4/metabolismo , Animais , Linhagem Celular Tumoral , Feminino , Radioisótopos de Gálio/química , Radioisótopos de Gálio/farmacocinética , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/farmacocinética , Humanos , Taxa de Depuração Metabólica , Camundongos SCID , Estrutura Molecular , Neoplasias/patologia , Peptídeos/síntese química , Peptídeos/farmacocinética , Peptídeos Cíclicos/química , Peptídeos Cíclicos/farmacocinética , Tomografia por Emissão de Pósitrons , Ligação Proteica , Receptores CXCR4/antagonistas & inibidores , Distribuição Tecidual , Transplante HeterólogoRESUMO
OBJECTIVE: This study was conducted in an attempt to use blood flow scintigraphy with 99mTc-hexakis-2-methyoxy-isobutylisonitrile (99mTc-MIBI) for the evaluation of the angiogenic effect of hepatocyte growth factor (HGF) plasmid in a rat model of hind limb ischemia. MATERIALS AND METHODS: The femoral artery of the left hind limb of each rat was ligated to create a model of hind limb ischemia. Three weeks later, HGF plasmid (1.5 mg/1.1 ml/body) or saline (1.1 ml/body) was administered intramuscularly into three sites of the ischemic hind limb. Two and 4 weeks after the treatment, blood flow through the hind limb was measured by 99mTc-MIBI scintigraphy. In addition, the number of capillary endothelial cells obtained by immunostaining for CD31 was counted. RESULTS: After 99mTc-MIBI scintigraphy in the HGF plasmid-treated group, the blood flow ratio increased significantly from the pretreatment ratio 63.8 to 73.4%, 2 weeks after treatment (P<0.05) and to 97.8%, 4 weeks after treatment (P<0.05). The number of CD31-positive endothelial cells was significantly higher in the HGF plasmid-treated group than in the control group. CONCLUSIONS: The experimental study using a rat model of hind limb ischemia showed usefulness of 99mTc-MIBI scintigraphy to evaluate the angiogenic effect of HGF plasmid treatment.