Purpose:To develop a clinically translatable method of cell labeling with zirconium 89 ( 89 Zr) and oxine to track cells with positron emission tomography (PET) in mouse models of cell-based therapy. Materials andMethods:This study was approved by the institutional animal care committee. 89Zr-oxine complex was synthesized in an aqueous solution. Cell labeling conditions were optimized by using EL4 mouse lymphoma cells, and labeling efficiency was examined by using dendritic cells (DCs) (n = 4), naïve (n = 3) and activated (n = 3) cytotoxic T cells (CTLs), and natural killer (NK) (n = 4), bone marrow (n = 4), and EL4 (n = 4) cells. The effect of ] cells, n = 4) and by measuring the tumor size (n = 6). Two-way analysis of variance was used to compare labeling conditions, the Wilcoxon test was used to assess cell survival and proliferation, and Holm-Sidak multiple tests were used to assess tumor growth and perform biodistribution analyses. Results:89 Zr-oxine complex was synthesized at a mean yield of 97.3% 6 2.8 (standard deviation). It readily labeled cells at room temperature or 4°C in phosphate-buffered saline (labeling efficiency range, 13.0%-43.9%) and was stably retained (83.5% 6 1.8 retention on day 5 in DCs). Labeling did not affect the viability of DCs and CTLs when compared with nonlabeled control mice (P . .05), nor did it affect functionality. 89Zr-oxine complex enabled extended cell tracking for 7 days. Labeled tumor-specific CTLs accumulated in the tumor (4.6% on day 7) and induced tumor regression (P , .05 on day 7). Conclusion:We have developed a 89Zr-oxine complex cell tracking technique for use with PET that is applicable to a broad range of cell types and could be a valuable tool with which to evaluate various cell-based therapies.q RSNA, 2015
Using positron emission tomography (PET) imaging to monitor and quantitatively analyze the delivery and localization of Au nanomaterials (NMs), a widely used photothermal agent, is essential to optimize therapeutic protocols to achieve individualized medicine and avoid side effects. Coupling radiometals to Au NMs via a chelator faces the challenges of possible detachment of the radiometals as well as surface property changes of the NMs. In this study, we reported a simple and general chelator-free 64Cu radiolabeling method by chemically reducing 64Cu on the surface of polyethylene glycol (PEG)-stabilized Au NMs regardless of their shape and size. Our 64Cu-integrated NMs are proved to be radiochemically stable and can provide an accurate and sensitive localization of NMs through noninvasive PET imaging. We further integrated 64Cu onto arginine-glycine-aspartic acid (RGD) peptide modified Au nanorods (NRs) for tumor theranostic application. These NRs showed high tumor targeting ability in a U87MG glioblastoma xenograft model and were successfully used for PET image-guided photothermal therapy.
Single crystal X-ray diffraction show that Zr(IV) forms an octa-coordinated complex with 4 bidentate hydroxamates whose solution structures were investigated utilizing density functional theory at the level of B3LYP/DGDZVP. Stability constants obtained by potentiometry were in accordance with the tendency observed when radiolabeling with 89Zr.
CXCR4 is a chemokine receptor which has been shown to be exploited by various tumors for increased survival, invasion, and homing to target organs. We developed a one step radiosynthesis for labeling the CXCR4-specific antagonist AMD3100 with Cu-64 to produce 64 Cu-AMD3100 with a specific activity of 11.28 Ci/μmol (417 GBq/μmol) at the end of radiosynthesis. Incorporation of Cu(II) ion into AMD3100 did not change its ability to inhibit cellular migration in response to the (only) CXCR4 ligand, SDF-1/CXCL12. 64 Cu-AMD3100 binding affinity to CXCR4 was found to be 62.7 μM. Biodistribution of 64 Cu-AMD3100 showed accumulation in CXCR4-expressing organs and tissues, a renal clearance pathway, and an anomalous specific accumulation in the liver. We conclude that 64 Cu-AMD3100 exhibits promise as a potential PET imaging agent for visualization of CXCR4-positive tumors and metastases and might be used to guide and monitor anti-CXCR4 tumor therapy.
Purpose The success of hematopoietic stem cell transplantation (HSCT) depends on donor cell homing to the bone marrow (BM). However, there is no reliable method of noninvasively monitoring the kinetics and distribution of transferred cells. Using Zirconium-89 (89Zr)-oxine cell labeling combined with positron emission tomography (PET) imaging, we sought to visualize and quantify donor cell homing in a mouse BM transplantation model. Experimental Design The effect of 89Zr-oxine labeling on BM cell viability and differentiation was evaluated in vitro. 89Zr-labeled BM cells (2×107 cells, 16.6 kBq/106 cells) were transferred intravenously and serial microPET images were obtained (n=5). The effect of a CXCR4 inhibitor, plerixafor, (5 mg/kg) and granulocyte-colony stimulation factor (G-CSF, 2.5 μg) on BM homing and mobilization were examined (n=4). Engraftment of the transferred 89Zr-labeled cells was evaluated (n=3). Results 89Zr-oxine-labeled BM cells showed delayed proliferation, but differentiated normally. Transferred BM cells rapidly migrated to the BM, spleen, and liver (n=5). Approximately 36% of donor cells homed to the BM within 4 h, irrespective of prior BM ablation. Inhibition of CXCR4 by plerixafor alone or with G-CSF significantly blocked the BM homing (p<0.0001, vs non-treated, at 2 h), confirming a crucial role of the CXCR4-CXCL12 system. Mobilization of approximately 0.64% of pre-transplanted BM cells induced a 3.8-fold increase of circulating BM cells. 89Zr-labeled donor cells engrafted as well as non-labeled cells. Conclusions 89Zr-oxine PET imaging reveals rapid BM homing of transferred BM cells without impairment of their stem cell functions, and thus, could provide useful information for optimizing HSCT.
Cetuximab is a recombinant, human/mouse chimeric IgG1, monoclonal antibody (mAb) that binds to the epidermal growth factor receptor (EGFR/HER1). Cetuximab is approved for the treatment of patients with HER1-expressing metastatic colorectal cancer. Limitations in currently reported radiolabeled cetuximab for PET applications prompted the development of 86Y-CHX-A”-DTPA-cetuximab as an alternative for imaging HER1-expressing cancer. 86Y-CHX-A”-DTPA-cetuximab can also serve as a surrogate marker for 90Y therapy. Methods Bifunctional chelate, CHX-A”-DTPA was conjugated to cetuximab and radiolabeled with 86Y. In vitro immunoreactivity was assessed in HER1-expressing A431 cells. In vivo biodistribution, PET imaging and non-compartmental pharmacokinetics were performed on mice bearing HER1-expressing human colorectal (LS-174T and HT29), prostate (PC-3 and DU145), ovarian (SKOV3) and pancreatic (SHAW) tumor xenografts. Receptor blockage was demonstrated by co-injection of either 0.1 or 0.2 mg cetuximab. Results 86Y-CHX-A”-DTPA-cetuximab was routinely prepared with a specific activity of 1.5– 2 GBq/mg and in vitro immunoreactivity ranging from 65–75 %. Biodistribution and PET imaging studies demonstrated high HER1-specific tumor uptake of the radiotracer and clearance from non-specific organs. In LS-174T tumor bearing mice injected with the 86Y-CHX-A”-DTPA-cetuximab alone, 86Y-CHX-A”-DTPA-cetuximab plus 0.1 mg cetuximab or 0.2 mg cetuximab, the tumor uptake values at 3 d were 29.3 ± 4.2, 10.4 ± 0.5 and 6.4 ± 0.3 % ID/g, respectively, demonstrating dose-dependent blockage of the target. Tumors were clearly visualized 1 d after injecting 3.8–4.0 MBq 86Y-CHX-A”-DTPA-cetuximab. Quantitative PET revealed highest tumor uptake in LS-174T (29.55 ± 2.67 % ID/cc) and lowest tumor uptake in PC-3 (15.92 ± 1.55 % ID/cc) xenografts at 3 d after injection. Tumor uptake values quantified by PET were closely correlated (r2= 0.9, n=18) to values determined by biodistribution studies. Conclusion This study demonstrates the feasibility in preparation of high specific activity 86Y-CHX-A”-DTPA-cetuximab and its application for quantitative non-invasive PET imaging of HER1-expressing tumors. 86Y-CHX-A”-DTPA-cetuximab offers an attractive alternative to previously labeled cetuximab for PET and warrants further investigation for clinical translation.
The over-expression and -activation of hepatocyte growth factor receptor (Met) in various cancers has been linked to increased proliferation, progression to metastatic disease, and drug resistance. Developing a PET imaging agent to assess Met expression would aid in diagnosis and monitoring responses to Met-targeted therapies. In these studies Onartuzumab (MetMAb), the experimental therapeutic one-armed monoclonal antibody, was radiolabeled with 76Br or 89Zr and evaluated as an imaging agent in Met expressing cell lines and mouse xenografts. Methods 89Zr-df-Onartuzumab was synthesized using a desferrioxamine-Onartuzumab conjugate (df-Onartuzumab); 76Br-Onartuzumab was labeled directly. Met binding studies were performed using the human tumor-derived cell lines MKN-45, SNU-16 and U87-MG, which have relatively high, moderate and low levels of Met, respectively. Biodistribution and microPET imaging studies were performed in MKN-45 and U87-MG xenografts. Results 76Br-Onartuzumab and 89Zr-df-Onartuzumab exhibited specific, high affinity Met binding (nM) that was concordant with established Met expression levels. In MKN-45 (gastric carcinoma) xenografts, both tracers cleared slowly from non-target tissues with the highest uptakes in tumor, blood, kidney, and lung. 76Br-Onartuzumab MKN-45 tumor uptakes remained relatively constant from 18 h (5%ID/g) to 48 h (3%ID/g) and exhibited tumor:muscle ratios ranging from 4:1 to 6:1. In contrast, 89Zr-df-Onartuzumab MKN-45 tumor uptake continued to accumulate from 18 h (10%ID/g) to 120 h (23%ID/g), attaining tumor:muscle ratios ranging from 20:1 to 27:1. MKN-45 tumors were easily visualized in imaging studies with both tracers at 18 h but after 48 h 89Zr-df-Onartuzumab image quality improved with at least 2 fold greater tumor uptakes compared to non-target tissues. MKN-45 tumor uptakes for both tracers correlated significantly with tumor mass and Met expression, and were not affected by the presence of plasma shed Met. Conclusions 89Zr-df-Onartuzumab and 76Br-Onartuzumab specifically targeted Met in vitro and in vivo; 89Zr-df-Onartuzumab achieved higher tumor uptakes and tumor:muscle ratios than 76Br-Onartuzumab at later times suggesting that 89Zr-df-Onartuzumab would be better suited to image Met for diagnostic and prognostic purposes.
Prostate cancer is the most frequently diagnosed malignant tumor in men worldwide. Prostate-specific membrane antigen (PSMA) is a surface molecule specifically expressed by prostate tumors that has been shown to be a valid target for internal radionuclide therapy in both preclinical and clinical settings. The most common radiotherapeutic agent is the small molecule Lu-PSMA-617, which is under clinical evaluation in multiple countries. Nevertheless, its efficacy in causing tumor regression is still suboptimal, even when administered in several cycles per patient, perhaps due to poor pharmacokinetics (PK), which limits uptake by the tumor cells. We postulated that the addition of the Evans blue (EB) moiety to PSMA-617 would improve the PK by extending circulation half-life, which would increase tumor uptake and improve radiotherapeutic efficacy. PSMA-617 was modified by conjugation of a 2-thiol acetate group onto the primary amine and thereafter reacted with a maleimide functional group of an EB derivative, to give EB-PSMA-617. The PK and radiotherapeutic efficacy ofY- or Lu-EB-PSMA-617 was compared to the clinically used radiopharmaceuticalY- or Lu- PSMA-617 in PC3-PIP tumor-bearing mice. EB-PSMA-617 retained binding to serum albumin as well as a high internalization rate by tumor cells. Upon injection, metal-labeled EB-PSMA-617 demonstrated an extended blood half-life compared to PSMA-617 and, thereby, prolonged the time window for binding to PSMA. The improved PK of EB-PSMA-617 resulted in significantly higher accumulation in PSMA tumors and highly effective radiotherapeutic efficacy. Remarkably, a single dose of 1.85 MBq of Y- orLu-EB-PSMA-617 was sufficient to eradicate established PMSA tumors in mice. No significant body weight loss was observed, suggesting little to no gross toxicity. The construct described here, EB-PSMA-617, may improve the radiotherapeutic efficacy for patients with PSMA-positive tumors by reducing both the amount of activity needed for therapy as well as the frequency of administration, as compared to PSMA-617.
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