Tumor Imaging Agent Research Articles

Development of a99mTc-Labeled CXCR4 Antagonist Derivative as a New Tumor Radiotracer

Due to high expression of CXCR4 (CXC chemokine receptor type 4) receptors in many tumors and metastasis, synthesis and labeling of CXCR4 receptor-targeted analogs as tumor imaging agents have been encouraged. Herein, CXCR4 receptor-targeted peptide antagonist was prepared and thereafter its labeling with 99mTc by a bifunctional chelating agent and tricine coligand was developed. Radiotracer purity, stability, and tumor cell binding were assessed. Bioevaluation of radiotracer was performed in mice bearing xenograft tumor. More than 95% labeling yield and stability up to 24 hours were observed. Radiotracer-related tumor accumulation was 3.61 ± 0.15% ID/g at 1 hour postinjection. High stability and specific tumor uptake are important characteristics of the radiotracer that could nominate this as a targeted imaging agent in the future.

The potential of radiolabeled chemotherapeutics in tumor diagnosis: Preliminary investigations with 68 Ga-gemcitabine.

Preclinical Research & Development Gemcitabine, a nucleoside analog, is a well-known chemotherapeutic drug that is used either alone or with other agents to treat a wide variety of cancers. The aim of the present work was to evaluate the potential of 68 Ga-labeled gemcitabine for its application in positron emission tomography (PET) imaging of tumorous lesions. Gemcitabine was coupled with p-NCS-benzyl-DOTA in order to facilitate radiolabeling with 68 Ga. The gemcitabine-p-NCS-benzyl-DOTA was radiolabeled with 68 Ga, obtained from a 68 Ge/68 Ga radionuclide generator. The radiolabeled product was characterized by high performance liquid chromatography (HPLC) and its tumor specificity was evaluated by biodistribution studies in Swiss mice bearing fibrosarcoma tumors. Preliminary bioevaluation study showed good tumor uptake within 1 hr post-administration [2.5% Injected Activity (IA) per g of tumor] with rapid renal clearance (>90% IA) and a high tumor to muscle ratio. 68 Ga-gemcitabine may have potential as a PET agent for tumor imaging.

PH-Responsive PEG-Doxorubicin-Encapsulated Aza-BODIPY Nanotheranostic Agent for Imaging-Guided Synergistic Cancer Therapy.

Synergistic cancer therapy is of great interest for multiple advantages, such as excellent targeting accuracy, low side effects, and enhanced therapeutic efficiency. Herein, a near-infrared photosensitizer aza-BODIPY (AB) with high singlet oxygen quantum yield (ΦΔ = 82%) is designed and synthesized. With Schiff's base obtained from condensation reaction between doxorubicin (DOX) and polyethylene glycol-benzaldehyde (PEG-CHO) as the polymer matrix, aza-BODIPY is encapsulated to afford hydrophilic nanoparticles (DAB NPs). The DAB NPs exhibit high reactive oxygen species (ROS) generation rate and outstanding photothermal conversion efficiency (η = 38.3%) under irradiation. In vivo fluorescence- and photothermal-imaging (PTI) results demonstrate that DAB NPs can specifically accumulate at tumor sites and serve as dual-modal imaging probe for cancer diagnosis. Particularly, triggered by acidic tumor microenvironment, the HCN bond of Schiff's base would be broken simultaneously, resulting in the efficient release of DOX from DAB NPs at tumor sites as well as enhancing the targeting performance of chemotherapeutics. Compared with free DOX and aza-BODIPY nanoparticles, DAB NPs can inhibit tumor growth more effectively through pH-responsive photodynamic/photothermal/chemo synergistic therapy. This report may also present a practicable strategy to develop a pH-responsive nanotheranostic agent for tumor targeting, imaging, and therapy.

Synthesis of 99mTc-Radiolabeled Uridine as a Potential Tumor Imaging Agent

Uridine, a pyrimidine nucleoside essential for the synthesis of RNA and biomembranes, was radiolabeled with 99mTc to obtain a potential tumor imaging agent. The maximal radiochemical yield of about 96.5%, as determined by paper chromatography and instant thin-layer chromatography, was reached under the following optimum conditions: 1 mg of uridine, 20 μg of SnCl2·2H2O as reducing agent, 20 mg of mannitol as a stabilizer, and pH 8. 99mTc-uridine is stable in vitro at room temperature for up to 6 h post labeling. The biodistrbution study in tumor-bearing mice shows high target-to-nontarget ratio. These results match with the high docking score of the complex on uridine phosphorylase enzyme. 99mTc-uridine shows promise as a tumor imaging agent.

Preparation, in vitro and in vivo evaluation, and molecular dynamics (MD) simulation studies of novel F-18 labeled tumor imaging agents targeting focal adhesion kinase (FAK).

Focal adhesion kinase (FAK) has been identified as a promising target in the early diagnosis and therapy of tumor. In this work, we obtained and evaluated another two novel pyrimidine-based F-18 labeled tumor imaging agents targeting FAK. Among them, the corresponding F-19 standards [19F]2, displayed inhibition of FAK with IC50 values of 57.1 nM (better than the results in our published work) and showed an good selectivity profile against some other kinds of cancer-related kinases. [18F]2 also had relatively good results in the in vivo biodistribution in S180-tumor-bearing mice, with tumor uptake of 5.40 ± 0.12 and 5.96 ± 0.09 % ID per g at 15 and 30 min post-injection, respectively. What's more, [18F]2 could be accumulated in tumor at 30 min post-injection, which could be observed from the coronal micro-PET images of mice bearing S180 tumor. In addition, the blocking study for the [18F]2 with PF-562271 (one of the well-known best selective FAK inhibitor), displayed distinct reduction in the uptake of the radiotracer in tumor at 30 min post-injection in mice, suggesting that the uptake of [18F]2 in tumor was due to FAK over-expression or high expression in tumor. And the results of the molecular dynamics (MD) simulations and the docking studies were in consistent with the changing trends of the interaction between the F-19 standards and the FAK. Finally, in order to further increase the uptake of the F-18 labeled tracer in tumor, the following points should arouse attention, which could also be considered as the new findings and contributions of this study to the field of the tumor imaging agents: (1) the F-18 labeled tumor radiotracers which have closer interaction with the FAK, should be further designed, via building of models such as 3D-QSAR model to make reasonable guidance to our drug design and consideration of some functional groups which have hydrogen-bonding or salt-bridge interactions with key residues in the kinase domain of FAK; (2) the F-18 radiotracers with better pharmacokinetic properties should be designed, via building of dynamic drug absorption and distribution model in different tissues, to predict whether the molecules have ideal absorption in tumor and low uptake in non-target tissues. The relevant study is being undertaken.

Construction of Multifunctional Fe3O4-MTX@HBc Nanoparticles for MR Imaging and Photothermal Therapy/Chemotherapy.

To accomplish effective cancer imaging and integrated therapy, the multifunctional nanotheranostic Fe3O4-MTX@HBc core-shell nanoparticles (NPs) were designed. A straightforward method was demonstrated for efficient encapsulation of magnetic NPs into the engineered virus-like particles (VLPs) through the affinity of histidine tags for the methotrexate (MTX)-Ni2+ chelate. HBc144-His VLPs shell could protect Fe3O4-MTX NPs from the recognition by the reticuloendothelial system as well as could increase their cellular uptake efficiency. Through our well-designed tactic, the photothermal efficiency of Fe3O4 NPs were obviously improved in vitro and in vivo upon near-infrared (NIR) laser irradiation. Moreover, Magnetic resonance imaging (MRI) results showed that the Fe3O4-MTX@HBc core-shell NPs were reliable T2-type MRI contrast agents for tumor imaging. Hence the Fe3O4-MTX@HBc core-shell NPs may act as a promising theranostic platform for multimodal cancer treatment.

Synthesis and evaluation of Tc-99m and fluorescence-labeled elastin-derived peptide, VAPG for multimodal tumor imaging in murine tumor model.

We developed a Tc-99m and fluorescence-labeled peptide, Tc-99m TAMRA-GHEG-ECG-VAPG to target tumor cells and evaluated the diagnostic performance as a dual-modality imaging agent for tumor in a murine model. TAMRA-GHEG-ECG-VAPG was synthesized by using Fmoc solid-phase peptide synthesis. Radiolabeling of TAMRA-GHEG-ECG-VAPG with Tc-99m was done by using ligand exchange via tartrate. Binding affinity and in vitro cellular uptake studies were performed. Gamma camera imaging, biodistribution, and ex vivo imaging studies were performed in murine models with SW620 tumors. Tumor tissue slides were prepared and analyzed with immunohistochemistry by using confocal microscopy. After radiolabeling procedures with Tc-99m, Tc-99m TAMRA-GHEG-ECG-VAPG complexes were prepared in high yield (>96%). The Kd of Tc-99m TAMRA-GHEG-ECG-VAPG determined by saturation binding was 16.8±3.6nM. Confocal microscopy images of SW620 cells incubated with TAMRA-GHEG-ECG-VAPG showed strong fluorescence in the cytoplasm. Gamma camera imaging revealed substantial uptake of Tc-99m TAMRA-GHEG-ECG-VAPG in tumors. Tumor uptake was effectively blocked by the coinjection of an excess concentration of VAPG. Specific uptake of Tc-99m TAMRA-GHEG-ECG-VAPG was confirmed by biodistribution, ex vivo imaging, and immunohistochemistry stain studies. In vivo and in vitro studies revealed substantial uptake of Tc-99m TAMRA-GHEG-ECG-VAPG in tumor cells. Tc-99m TAMRA-GHEG-ECG-VAPG has potential as a dual-modality tumor imaging agent.

Synthesis, 99m Tc-labeling, and preliminary biological evaluation of DTPA-melphalan conjugates.

Melphalan (MFL) is a typical nitrogen mustard for the treatment of many types of cancer. For the purpose to develop novel 99m Tc-labeled tumor imaging agents with SPECT, MFL was directly labeled by 99m Tc using diethylene triamine pentacetate acid (DTPA) as bifunctional chelating agent. The novel ligands were successfully synthesized by conjugation of DTPA to MFL to get monosubstituted DTPA-MFL and bis-substituted DTPA-2MFL. Radiolabeling was performed in high yield to get 99m Tc-DTPA-MFL and 99m Tc-DTPA-2MFL, respectively, which were hydrophilic and stable at room temperature. The high initial tumor uptake with retention, good tumor/muscle ratios, and satisfactory scintigraphic images suggested the potential of 99m Tc-DTPA-MFL and 99m Tc-DTPA-2MFL for tumor imaging. However, the slow normal tissue clearance would be a great obstacle. Further modification on the linker and/or 99m Tc-chelate to improve the tumor targeting efficacy and in vivo kinetic profiles is currently in progress.

A novel radiolabeled indole derivative as solid tumor imaging agent: in silico and preclinical pharmacological study

Biologically active indole derivative was synthesized and screened for its cytotoxicity against breast cancer cell line (MCF-7) with the IC50 equals 17.5 µg/mL. Docking study showed its high binding affinity to the COX-2 enzyme. It’s radiolabeling with 99mTc and showed high radiochemical yield (92.10 ± 0.57%) and in vitro stability in serum up to 10 h. Biodistribution studies of a novel 99mTc-NSIC complex in tumor-bearing mice showed high T/NT ratio (6.17 ± 0.08 at 30 min. post-injection), suggesting this complex could be used as a solid tumor imaging agent.

Preparation and preclinical evaluation of radioiodinated secnidazole as a possible tumor imaging agent

To develop a radiopharmaceutical localizing in tumor hypoxic tissues, secnidazole (SECN) was labeled with 125I. The labeled product was prepared with the radiochemical yield higher than 96% when performing the reaction at 45°C for 30 min. The electrophilic radioiodination of SECN was done using different oxidizing agents. Iodogen appeared to be more effective than chloramine-T (CAT) and N-bromosuccinimide (NBS). 125I-SECN was tested in vivo with a tumor model prepared by the intramuscular injection of Ehrlich cell line into the thigh muscle of mice. 125I-SECN showed high accumulation in tumor hypoxic tissue (3.6% of injected dose per gram of organ at 2 h post injection). The target/nontarget (T/NT) ratio was high (T/NT = 6 at 24 h post injection). Thus, radioiodinated SECN shows promise as a selective imaging agent for diagnosis of tumor hypoxia.

Synthesis, radiolabeling and biological distribution of a new dioxime derivative as a potential tumor imaging agent

A novel dioxime derivative (2E,2′E,3E,3′E)-3,3′-(pyrimidine-4,5-diylbis(azanylylidene))bis(butan-2-one)dioxime was synthesized with a yield of 65%. IR, elemental analysis, mass spectroscopy and 1H-NMR were used to characterize the structure of the synthesized compound. 99mTc-dioxime was radio-synthesized with a high radiochemical yield of 97.8 ± 0.5% and in vitro stability of 6 h under the optimum conditions. The preclinical evaluation of 99mTc-dioxime in solid tumor-bearing mice showed high accumulation in solid tumor cells with a high Target/Non-Target ratio of 5.14 at 30 min post-injection. This study suggests that 99mTc-dioxime derivative is a promising candidate as a new 99mTc-based tumor-imaging agent after further preclinical studies.

Preparation and Identification of HER2 Radioactive Ligands and Imaging Study of Breast Cancer-Bearing Nude Mice

OBJECTIVE: A micro-molecule peptide TP1623 of 99mTc-human epithelial growth factor receptor 2 (HER2) was prepared and the feasibility of using it as a HER2-positive molecular imaging agent for breast cancer was evaluated. METHODS: TP1623 was chemically synthesized and labeled with 99mTc. The labeling ratio and stability were detected. HER2 expression levels of breast cancer cells (SKBR3 and MDA-MB-231) and cell binding activity were measured. Biodistribution of 99mTC-TP1623 in normal mice was detected. SKBR3/MDA-MB-231-bearing nude mice models with high/low expressions of HER2 were established. Tumor tissues were stained with hematoxylin–eosin (HE) and measured by immunohistochemistry to confirm the formation of tumors and HER2 expression. SPECT imaging was conducted for HER2-overexpressing SKBR3-bearing nude mice. The T/NT ratio was calculated and compared with that of MDA-MB-231-bearing nude mice with low HER2 expression. The competitive inhibition image was used to discuss the specific binding of 99mTc- TP1623 and the tumor. RESULTS: The labeling ratio of 99mTc-TP1623, specific activity, and radiochemical purity (RCP) after 6 h at room temperature were (97.39 ± 0.23)%, (24.61 ± 0.06) TBq/mmol, and (93.25 ± 0.06)%, respectively. HER2 of SKBR3 and MDA-MB-231 cells showed high and low expression levels by immunohistochemistry, respectively. The in vitro receptor assays indicated that specific binding of TP1623 and HER2 was retained. Radioactivity in the brain was always at the lowest level, while the clearance rate of blood and the excretion rate of the kidneys were fast. HE staining showed that tumor cells were observed in SKBR3- and MDA-MB-231-bearing nude mice, with significant heteromorphism and increased mitotic count. The imaging of mice showed that targeted images could be made of 99mTc-TP1623 in high HER2-expressing tumors, while no obvious development was shown in tumors in low HER2-expressing nude mice. No development was visible in tumors in competitive inhibition of imaging, which indicates the combination of 99mTc-TP1623 and tumor was mediated by HER2. CONCLUSION: High labeling ratio and specific activity of 99mTc-TP1623 is successfully prepared; it is a molecular imaging agent for HER2-positive tumors that has potential applicative value.

99mTc-labeled PSMA inhibitor: Biokinetics and radiation dosimetry in healthy subjects and imaging of prostate cancer tumors in patients

The prostate-specific membrane antigen (PSMA) is expressed in epithelial cells of the prostate and highly overexpressed in 95% of advanced prostate cancers. The aims of this study was to estimate the biokinetics and dosimetry of 99mTc-EDDA/HYNIC-iPSMA (99mTc-labeled PSMA inhibitor) in eight healthy subjects and evaluate its usefulness as a tumor-imaging agent in eight prostate cancer patients. Methods99mTc-EDDA/HYNIC-iPSMA was obtained from a lyophilized formulation with radiochemical purities >98%, determined by reversed-phase HPLC and ITLC-SG analyses. Whole-body images from eight healthy subjects were acquired at 20min, and at 2, 6 and 24h after 99mTc-EDDA/HYNIC-iPSMA administration. Regions of interest (ROIs) were drawn around the source organs on each time frame. Each ROI was corrected by background, attenuation, scattered radiation and physical decay. The image sequence was used to extrapolate the 99mTc-EDDA/HYNIC-iPSMA time–activity curves of each organ to adjust the biokinetic model and calculate the total number of disintegrations (N) that occurred in the source regions. N data were the input for the OLINDA/EXM code to calculate internal radiation doses. In eight prostate cancer patients with histologically confirmed cancer, whole-body SPECT/CT images were obtained at 3h. ResultsThe blood activity showed a half-life value of 4.98min for the fast component (T1/2α=ln2/8.34), 2.49h for the first slow component (T1/2β=ln2/0.278), and 9.24h for the second slow component (T1/2γ=ln2/0.076). Images from patients showed an average tumor/background ratio of 8.99±3.27 at 3h. The average equivalent doses calculated for a study using 740MBq were 3.80, 7.06, 9.69, 10.70, and 28.80mSv for the breast, spleen, salivary glands, liver, and kidneys respectively, with an effective dose of 3.42±0.78mSv. ConclusionsAll the absorbed doses were comparable to those known for most of the 99mTc studies. 99mTc-EDDA/HYNIC-iPSMA obtained from kit formulations showed high tumor uptake in patients with malignant lesions, making it a promising imaging radiopharmaceutical to target site-specific prostate cancer.

99mTc-radiolabeled GE11-modified peptide for ovarian tumor targeting

BackgroundOvarian cancer is a serious threat for women health and the early diagnosis of this cancer might improves the survival rate of patients. The use of the targeted radiopharmaceuticals could be a non-invasive and logical method for tumor imaging. The aim of this study was to radiolabel GE11 peptide as a new specific probe for imaging of ovarian tumor.MethodsHYNIC-SSS-GE11 peptide was labeled with 99mTc using tricine as a coligand. The 99mTc-tricine-HYNIC-SSS-GE11 peptide was evaluated for specific cellular binding in three cell lines with different levels of EGFR expression. Tumor targeting was assessed in SKOV3 tumor bearing mice.ResultsBy using tricine as a coligand, labeling yield was more than 98% and the stability of the radiolabelled peptide in human serum up to 4 h was 96%. The in vitro cell uptake test showed that this radiolabeled peptide had a good affinity to SKOV3 cells with dissociation constant of 73 nM. The in vivo results showed a tumor/muscle ratio of 3.2 at 4 h following injection of 99mTc-tricine-HYNIC-SSS-GE11 peptide.ConclusionsResults of this study showed that 99mTc-tricine-HYNIC-SSS-GE11 peptide could be a promising tool for diagnosis and staging of ovarian cancer.Graphical 99mTc-tricine-HYNIC-SSS-GE11, a novl targeted agent for ovarian tumor imaging

Radioiodination of 3-amino-2-quinoxalinecarbonitrile 1,4-dioxide and its biological distribution in Erhlich ascites cancer bearing mice as a preclinical tumor imaging agent

3-Amino-2-quinoxalinecarbonitrile 1,4-dioxide (QN) was labeled with 125I, and the biological distribution of the product was studied. 125I-QN was prepared by direct electrophilic substitution reaction using N-bromosuccinimide (NBS) as an oxidizing agent. The radiochemical yield of 92% was reached under the following optimum conditions: pH 7, 15 min, 100 μg of QN, and 75 μg of NBS. The labeled QN was stable for up to 12 h post labeling. Biodistribution study of 125I-QN in tumor-bearing mice reflected that it accumulated in tissues with high proliferation rate with preferential accumulation in tumor sites. 125I-QN was incorporated rapidly in the tumor site (T/NT = 4 at 2 h post injection), and then its content slowly decreased, whereas in the other tissues it decreased rapidly. The results obtained encourage the use of 123I-QN as a tumor imaging agent.

Primary study on fluro [ 19F] berberine derivative for human hepatocellular carcinoma targetting in vitro

[ 18F]HX-01, a Fluorine-18 labeled berberine derivative, is a potential positron emission tomography (PET) tumor imaging agent, while [ 19F]HX-01 is a nonradioactive reference substance with different energy state and has the same physical and chemical properties. In order to collect data for further study of [ 18F]HX-01 PET imaging of hepatocellular carcinoma in vivo, this study compared the uptake of [ 19F]HX-01 by human hepatocellular carcinoma and normal hepatocytes in vitro. The target compound, [ 19F]HX-01, was synthesized in one step using berberrubine and 3-fluoropropyl 4-methylbenzenesulfonate. Cellular uptake and localization of [ 19F]HX-01 were performed by a fluorescence microscope in human hepatocellular carcinoma HepG2, SMMC-7721 and human normal hepatocyte HL-7702. Cellular proliferation inhibition and cell cytotoxicity assay of the [ 19F]HX-01 were conducted using cell counting kit-8 (CCK-8) on HepG2, SMMC-7721 and HL-7702 cells. Fluorescent microscopy showed that the combining ability of [ 19F]HX-01 to the carcinoma SMMC-7721 and HepG2 was higher than that to the normal HL-7702. Cellular proliferation inhibition assay demonstrated that [ 19F]HX-01 leaded to a dose-dependent inhibition on SMMC-7721, HepG2, and HL-7702 proliferation. Cell cytotoxicity assay presented that the cytotoxicity of [ 19F]HX-01 to SMMC-7721 and HepG2 was obviously higher than that to HL-7702. This in vitro study showed that [ 19F]HX-01 had a higher selectivity on human hepatocellular carcinoma cells (SMMC-7721, HepG2) but has less toxicity to normal hepatocytes (HL-7702). This could set up the idea that the radioactive reference substance [ 18F]HX-01 may be worthy of further development as a potential molecular probe targeting human hepatocellular carcinoma using PET.

Synthesis and Preliminary Evaluation of 5-[18F]fluoroleucine.

Amino acid transporters, such as LAT1, are overexpressed in aggressive prostate and breast carcinomas, directly influencing pathways of growth and proliferation. The purpose of this study was to synthesize and characterize a novel 18F labeled leucine analog, 5-[18F]fluoroleucine, as a potential imaging agent for aggressive tumors which may not be amenable to imaging by FDG PET. 5-fluoroleucine was synthesized and characterized, and its 18F-labeled analog was synthesized from a mesylate precursor. First, breast cancer cell line assays were performed to evaluate uptake of 3H- or 14C-labeled L-leucine and other essential amino acids. Both L-leucine and 5- [18F]fluoroleucine were tested for uptake and accumulation over time, and for uptake via LAT1. Biodistribution studies were performed to estimate radiation dosimetry for human studies. Small animal PET / CT studies of a breast cancer were performed to evaluate in vivo 5-[18F]fluoroleucine tumor uptake. Breast cancer cell lines showed increasing high net accumulation of L-[14C]leucine. Both L-leucine and 5-[18F]fluoroleucine showed increasing uptake over time in in vitro tumor cell assays, and uptake was also shown to occur via LAT1. The biodistribution study of 5-[18F]fluoroleucine showed rapid renal excretion, no significant in vivo metabolism, and acceptable dosimetry for use in humans. In vivo small animal PET / CT imaging of a breast cancer xenograft showed uptake of 5- [18F]fluoroleucine in the tumor, which progressively increased over time. 5-[18F]fluoroleucine is a leucine analog which may be useful in identifying tumors with high or upregulated expression of amino acid transporters, providing additional information that may not be provided by FDG PET.

Synthesis of novel PEG-modified nitroimidazole derivatives via “hot-click” reaction and their biological evaluation as potential PET imaging agent for tumors

Ten novel PEG-modified nitroimidazole derivatives labeled with 18F were synthesized via “hot-click” reaction and evaluated as PET tumor tracers. The radiolabeling method was convenient and efficient, all compounds displayed high radiochemical purity (>95%), high yield (30–50%) and good stability in saline and human serum. The biodistribution studies in EMT-6 tumor-bearing mice demonstrated their tumor uptake values at 60 min postinjection were 1.46–2.99%ID/g, which were lower than [18F]FMISO (5.43%ID/g), their tumor-to-liver ratios were 0.73–1.07, higher than [18F]FMISO (0.69). In vitro MCF-7 cell uptake studies showed their uptake values have no significant difference between hypoxic and aerobic cells.

Abstract P3-13-08: Preclinical validation of a new tumor imaging agent targeting αvβ3 to detect breast tumor using NIR-light imaging

Abstract Surgery is still a essential step for breast cancer treatment. Complete tumor removal during surgery rely on surgeon's ability to differentiate tumor from normal tissue. To date, no intra operative method is available and reliable enough to help the surgeon delineate precisely tumor extension in the adjacent normal tissue. Thus, surgeons rely solely on pre operative imaging techniques to delineate tumor margins. Recent advances made in the field of non-invasive imaging and vectorized nano-size particles have revealed a remarkable potential for improved tumor-margin detection. AngiostampTM is a new fluorescent agent for intra operative imaging. This system provides strong binding on αvβ3 integrin-rich tumor neoangiogenesis. Our general hypothesis is that targeting αvβ3 integrin-rich breast carcinoma neoangiogenesis should provide improved delivery of diagnostic compounds and assist surgeons intra operatively using near-infrared imaging techniques. We conducted preclinical studies to evaluate the distribution of angiostampTM in vivo in murine breast tumor model and to determine the expression of αvβ3 integrin on human breast specimens. The capacity of AngiostampTM to target αvβ3 integrin was assessed in 4T1 breast tumor model. After tumor implantation, mices were injected with AngiostampTM or a saline solution. Detection of the tumors was performed at different timepoints (early, progressive and established tumors, N= 24 mices/timepoint) using near infrared (NIR) imaging system (FluobeamTM) to detect fluorescence in tumor tissue. In parallel, the expression of αvβ3 integrins in normal breast tissue, benign lesions (N=20) and various tumors subtypes (N=120) was assessed by immunohistochemistry. In mice injected with AngiostampTM, fluorescence was observed only within the tumors with low background. AngiostampTM labeled tumors at all timepoint. No false negative fluorescence was found as confirmed by histopathological analyses. In humans, the αvβ3 integrin are expressed in normal breast epithelial cells and benign metaplastic or proliferative epithelial lesions. However, due to the density of carcinomatous cells, the level of expression was much higher in breast cancer: 94% of invasive ductal carcinomas and 100% of invasive lobular carcinomas had a membranous staining (moderate to high intensity). Expression in breast cancer was not restricted to tumor subtypes neither hormone receptor expression nor SBR grade. Based on this preclinical demonstration, AngiostampTM could allow a better intra-operative detection of tumor bed in breast cancer, increasing the efficiency of surgical procedure especially for infraclinic disease and decreasing the rate of second surgery. Preclinical development is ongoing and the first clinical trial is expected in 2017. Citation Format: Beurrier F, Dutour A, Chen Y, Froc E, Gayet P, Guillermet S, Rizo P, Chopin N, Faure C, Dammaco MA, Klinger S, Ferraioli D, Garin G, Treilleux I. Preclinical validation of a new tumor imaging agent targeting αvβ3 to detect breast tumor using NIR-light imaging [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-13-08.

Macrocyclic triamine derived glucose analogues for 99mTc(CO)3 labeling: synthesis and biological evaluation as potential tumor‐imaging agents

[99m Tc(CO)3 (H2 O)3 ]+ has attracted great attention among 99m Tc-labeling techniques, due to its ease of preparation, readily substituted water molecules of the precursor fac-[99m Tc(CO)3 (H2 O)3 ]+ by a variety of functional groups, small size and inertness. Bifunctional chelator based on a macrocyclic polyamine framework shows easy complexation with [99m Tc(CO)3 (H2 O)3 ]+ to produce stable complex. In this study, two novel 1, 5, 9-triazacyclododecane derivatives containing a glucose group (6 and 7) were successfully synthesized by reacting different glucose-azides with alkyne-[12]aneN3 via the so-called click chemistry and radiolabeled with [99m Tc(CO)3 (H2 O)3 ]+ to form 99m Tc(CO)3 -6 (C-1-substituted complex) and 99m Tc(CO)3 -7 (C-2-substituted complex) in high yields. The complexes were stable in vitro over 6h when incubated in saline at room temperature and in mouse serum at 37°C. The partition coefficient results showed that they were hydrophilic. The biodistribution studies in Kunming mice bearing S 180 tumor showed both complexes showed accumulation in the tumor. Between them, 99m Tc(CO)3 -7 had the advantages of much higher tumor uptake and tumor/muscle ratio. Compared with other reported 99m Tc-radiolabeled glucose derivatives, 99m Tc(CO)3 -7 also showed a higher tumor uptake and tumor/muscle ratio, suggesting it would be a potential candidate for further development as a tumor-imaging agent.