17 research outputs found
Therapy-Induced Changes in CXCR4 Expression in Tumor Xenografts Can Be Monitored Noninvasively with N-[C-11]Methyl-AMD3465 PET
Purpose Chemokine CXCL12 and its receptor CXCR4 are constitutively overexpressed in human cancers. The CXCL12-CXCR4 signaling axis plays an important role in tumor progression and metastasis, but also in treatment-induced recruitment of CXCR4-expressing cytotoxic immune cells. Here, we aimed to demonstrate the feasibility of N-[C-11]methyl-AMD3465 positron emission tomography (PET) to monitor changes in CXCR4 density in tumors after single-fraction local radiotherapy or in combination with immunization. Procedure TC-1 cells expressing human papillomavirus antigens E6 and E7 were inoculated into the C57BL/6 mice subcutaneously. Two weeks after tumor cell inoculation, mice were irradiated with a single-fraction 14-Gy dose of X-ray. One group of irradiated mice was immunized with an alpha-viral vector vaccine, SFVeE6,7, and another group received daily injections of the CXCR4 antagonist AMD3100 (3 mg/kg -intraperitoneal (i.p.)). Seven days after irradiation, all animals underwent N-[C-11]methyl-AMD3465 PET. Results PET imaging showed N-[C-11]methyl-AMD3465 uptake in the tumor of single-fraction irradiated mice was nearly 2.5-fold higher than in sham-irradiated tumors (1.07 +/- 0.31 %ID/g vs. 0.42 +/- 0.05 % ID/g, p <0.01). The tumor uptake was further increased by 4-fold (1.73 +/- 0.17 % ID/g vs 0.42 +/- 0.05 % ID/g, p <0.01) in mice treated with single-fraction radiotherapy in combination with SFVeE6,7 immunization. Administration of AMD3100 caused a 4.5-fold reduction in the tracer uptake in the tumor of irradiated animals (0.24 +/- 0.1 % ID/g, p <0.001), suggesting that tracer uptake is indeed due to CXCR4-mediated chemotaxis. Conclusion This study demonstrates the feasibility of N-[C-11]methyl-AMD3465 PET imaging to monitor treatment-induced changes in the density of CXCR4 receptors in tumors and justifies further evaluation of CXCR4 as a potential imaging biomarker for evaluation of anti-tumor therapies
Therapy-Induced Changes in CXCR4 Expression in Tumor Xenografts Can Be Monitored Noninvasively with N-[C-11]Methyl-AMD3465 PET
Purpose Chemokine CXCL12 and its receptor CXCR4 are constitutively overexpressed in human cancers. The CXCL12-CXCR4 signaling axis plays an important role in tumor progression and metastasis, but also in treatment-induced recruitment of CXCR4-expressing cytotoxic immune cells. Here, we aimed to demonstrate the feasibility of N-[C-11]methyl-AMD3465 positron emission tomography (PET) to monitor changes in CXCR4 density in tumors after single-fraction local radiotherapy or in combination with immunization. Procedure TC-1 cells expressing human papillomavirus antigens E6 and E7 were inoculated into the C57BL/6 mice subcutaneously. Two weeks after tumor cell inoculation, mice were irradiated with a single-fraction 14-Gy dose of X-ray. One group of irradiated mice was immunized with an alpha-viral vector vaccine, SFVeE6,7, and another group received daily injections of the CXCR4 antagonist AMD3100 (3 mg/kg -intraperitoneal (i.p.)). Seven days after irradiation, all animals underwent N-[C-11]methyl-AMD3465 PET. Results PET imaging showed N-[C-11]methyl-AMD3465 uptake in the tumor of single-fraction irradiated mice was nearly 2.5-fold higher than in sham-irradiated tumors (1.07 +/- 0.31 %ID/g vs. 0.42 +/- 0.05 % ID/g, p <0.01). The tumor uptake was further increased by 4-fold (1.73 +/- 0.17 % ID/g vs 0.42 +/- 0.05 % ID/g, p <0.01) in mice treated with single-fraction radiotherapy in combination with SFVeE6,7 immunization. Administration of AMD3100 caused a 4.5-fold reduction in the tracer uptake in the tumor of irradiated animals (0.24 +/- 0.1 % ID/g, p <0.001), suggesting that tracer uptake is indeed due to CXCR4-mediated chemotaxis. Conclusion This study demonstrates the feasibility of N-[C-11]methyl-AMD3465 PET imaging to monitor treatment-induced changes in the density of CXCR4 receptors in tumors and justifies further evaluation of CXCR4 as a potential imaging biomarker for evaluation of anti-tumor therapies.</p
Evaluation of N-[C-11]Methyl-AMD3465 as a PET Tracer for Imaging of CXCR4 Receptor Expression in a C6 Glioma Tumor Model
The chemokine receptor CXCR4 and its ligand CXCL12 play an important role in tumor progression and metastasis. CXCR4 receptors are expressed by many cancer types and provide a potential target for treatment. Noninvasive detection of CXCR4 may aid diagnosis and improve therapy selection. It has been demonstrated in preclinical studies that positron emission tomography (PET) with a radiolabeled small molecule could enable noninvasive monitoring of CXCR4 expression. Here, we prepared N-[C-11]methyl-AMD3465 as a new PET tracer for CXCR4. N-[C-11]Methyl-AMD3465 was readily prepared by N-methylation with [C-11]CH3OTf. The tracer was obtained in a 60 +/- 2% yield (decay corrected), the purity of the tracer was >99%, and specific activity was 47 +/- 14 GBq/mu mol. Tracer stability was tested in vitro using liver microsomes and rat plasma; excellent stability was observed. The tracer was evaluated in rat C6 glioma and human PC-3 cell lines. In vitro cellular uptake of N-[C-11]methyl-AMD3465 was receptor mediated. The effect of transition metal ions (Cu2+, Ni2+, and Zn2+) on cellular binding was examined in C6 cells, and the presence of these ions increased the cellular binding of the tracer 9-, 7-, and 3-fold, respectively. Ex vivo biodistribution and PET imaging of N-[C-11]methyl-AMD3465 were performed in rats with C6 tumor xenografts. Both PET and biodistribution studies demonstrated specific accumulation of the tracer in the tumor (SUV 0.6 +/- 0.2) and other CXCR4 expressing organs, such as lymph node (1.5 +/- 0.2), liver (8.9 +/- 1.0), bone marrow (1.0 +/- 0.3), and spleen (1.0 +/- 0.1). Tumor uptake was significantly reduced (66%, p <0.01) after pretreatment with Plerixafor (AMD3100). Biodistribution data indicates a tumor-to-muscle ratio of 7.85 and tumor-to-plasma ratio of 1.14, at 60 min after tracer injection. Our data demonstrated that N-[C-11]methyl-AMD3465 is capable of detecting physiologic CXCR4 expression in tumors and other CXCR4 expressing tissues. These results warrant further evaluation of N-[C-11]methyl-AMD3465 as a potential PET tracer for CXCR4 receptor imaging
Noninvasive monitoring of cancer therapy induced activated T cells using [F-18]FB-IL-2 PET imaging
Cancer immunotherapy urgently calls for methods to monitor immune responses at the site of the cancer. Since activated T lymphocytes may serve as a hallmark for anticancer responses, we targeted these cells using the radiotracer N-(4-[F-18] fluorobenzoyl)-interleukin-2 ([F-18] FB-IL-2) for positron emission tomography (PET) imaging. Thus, we noninvasively monitored the effects of local tumor irradiation and/or immunization on tumor-infiltrating and systemic activated lymphocytes in tumor-bearing mice. A 10- and 27-fold higher [F-18] FB-IL-2 uptake was observed in tumors of mice receiving tumor irradiation alone or in combination with immunization, respectively. This increased uptake was extended to several non-target tissues. Administration of the CXCR4 antagonist AMD3100 reduced tracer uptake by 2.8-fold, indicating a CXCR4-dependent infiltration of activated T lymphocytes upon cancer treatment. In conclusion, [F-18] FB-IL-2 PET can serve as a clinical biomarker to monitor treatment-induced infiltration of activated T lymphocytes and, on that basis, may guide cancer immunotherapies
Evaluation of <i>N</i>‑[<sup>11</sup>C]Methyl-AMD3465 as a PET Tracer for Imaging of CXCR4 Receptor Expression in a C6 Glioma Tumor Model
The chemokine receptor CXCR4 and
its ligand CXCL12 play an important
role in tumor progression and metastasis. CXCR4 receptors are expressed
by many cancer types and provide a potential target for treatment.
Noninvasive detection of CXCR4 may aid diagnosis and improve therapy
selection. It has been demonstrated in preclinical studies that positron
emission tomography (PET) with a radiolabeled small molecule could
enable noninvasive monitoring of CXCR4 expression. Here, we prepared <i>N</i>-[<sup>11</sup>C]methyl-AMD3465 as a new PET tracer for
CXCR4. <i>N</i>-[<sup>11</sup>C]Methyl-AMD3465 was readily
prepared by <i>N</i>-methylation with [<sup>11</sup>C]CH<sub>3</sub>OTf. The tracer was obtained in a 60 ± 2% yield (decay
corrected), the purity of the tracer was >99%, and specific activity
was 47 ± 14 GBq/μmol. Tracer stability was tested <i>in vitro</i> using liver microsomes and rat plasma; excellent
stability was observed. The tracer was evaluated in rat C6 glioma
and human PC-3 cell lines. <i>In vitro</i> cellular uptake
of <i>N</i>-[<sup>11</sup>C]methyl-AMD3465 was receptor
mediated. The effect of transition metal ions (Cu<sup>2+</sup>, Ni<sup>2+</sup>, and Zn<sup>2+</sup>) on cellular binding was examined in
C6 cells, and the presence of these ions increased the cellular binding
of the tracer 9-, 7-, and 3-fold, respectively. <i>Ex vivo</i> biodistribution and PET imaging of <i>N</i>-[<sup>11</sup>C]methyl-AMD3465 were performed in rats with C6 tumor xenografts.
Both PET and biodistribution studies demonstrated specific accumulation
of the tracer in the tumor (SUV 0.6 ± 0.2) and other CXCR4 expressing
organs, such as lymph node (1.5 ± 0.2), liver (8.9 ± 1.0),
bone marrow (1.0 ± 0.3), and spleen (1.0 ± 0.1). Tumor uptake
was significantly reduced (66%, <i>p</i> < 0.01) after
pretreatment with Plerixafor (AMD3100). Biodistribution data indicates
a tumor-to-muscle ratio of 7.85 and tumor-to-plasma ratio of 1.14,
at 60 min after tracer injection. Our data demonstrated that <i>N</i>-[<sup>11</sup>C]methyl-AMD3465 is capable of detecting
physiologic CXCR4 expression in tumors and other CXCR4 expressing
tissues. These results warrant further evaluation of <i>N</i>-[<sup>11</sup>C]methyl-AMD3465 as a potential PET tracer for CXCR4
receptor imaging
Non-invasive imaging of kupffer cell status using radiolabelled mannosylated albumin
Objectives Kupffer cells (KCs) play a key role in maintaining liver homeostasis, hepatotoxicity and in liver pathology, but their functional status cannot be directly assessed in vivo (1-5). We report a PET tracer for noninvasive translational imaging of KCs. Methods A mannosylated human serum albumin (18mHSA), that binds to CD206 receptor [on KCs and M2-macrophages(6-7)], was synthesized, labelled by conjugation with N-succinimidyl 4-[18F]fluorobenzoate ([18F]FB). Pharmacological properties of [18F]FB18mHSA were investigated by ex vivo biodistribution and blocking studies at 30, 60 min (n=5). A 60min dynamic PET imaging studies with arterial blood sampling were performed in rats after injection of ~15 MBq of [18F]FB18mHSA (n=5). Results [18F]FB18mHSA was stable rat plasma in vitro, but showed significant metabolism in vivo (16% parent at 60 min). Radioactivity in blood decreased from the first time-point (10 sec) onward. Ex vivo biodistribution showed hepatic uptake was high (SUV 11.4±2.4 (mean±SD) at 30 min; SUV 8.9±3.3 at 60 min), as was accumulation in the kidney (SUV 24±7), due to metabolism in liver and rapid clearance of radioactivity from the blood pool via renal-urinary route. Blocking with a 20 fold excess of the unlabelled 18-mHSA, significantly decreased the uptake in liver (SUV 0.8±1.2 at 30 min, p<0.0005; SUV 4.5±0.7 at 60 min; p<0.05) and organs with immune function like bone-marrow (84%, p<0.0005) and spleen (90%, p<0.0005). PET data was analysed by Logan and Patlak graphical analysis using the metabolite-corrected plasma curve. Data was well described by Logan model, but not by Patlak model, indicating reversible binding kinetics. Conclusions [18F]FB18mHSA allows quantitative noninvasive PET imaging of the KCs and this novel method might be useful to investigate liver toxicity and fibrosis