Tumor Imaging Agent Research Articles

Upconversion nanoparticle as a theranostic agent for tumor imaging and therapy

Upconversion nanoparticles (UCNPs) as a promising material are widely studied due to their unique optical properties. The material can be excited by long wavelength light and emit visible wavelength light through multiphoton absorption. This property makes the particles highly attractive candidates for bioimaging and therapy application. This review aims at summarizing the synthesis and modification of UCNPs, especially the applications of UCNPs as a theranostic agent for tumor imaging and therapy. The biocompatibility and toxicity of UCNPs are also further discussed. Finally, we discuss the challenges and opportunities in the development of UCNP-based nanoplatforms for tumor imaging and therapy.

Molecular Targeted Magnetic Resonance Imaging of Human Colorectal Carcinoma (LoVo) Cells Using Novel Superparamagnetic Iron Oxide- Loaded Nanovesicles: In Vitro and in vivo Studies

To investigate the feasibility of superparamagnetic iron oxide (SPIO) nanoparticles (SPIO) as a magnetic resonance (MR) contrast agent to enhance tumor imaging in vivo. Hydrophobic SPIO (oil-soluble SPIO; OSPIO) and hydrophilic SPIO (water-soluble SPIO; WSPIO) were loaded in methoxy-poly(ethylene glycol)-block-poly(D,L-lactic acid) (PEG-PDLLA) nanovesicles. Three groups of nude mice (n=12/group) xenografted with human colorectal carcinoma (LoVo) cells were injected into the caudal vein with WSPIO, OSPIO-loaded nanovesicles, or WSPIO-loaded nanovesicles. MRI scans were performed on all of the mice, and the relative T2 values were measured in the tumor and the liver. The differences in these T2 values between the three groups were compared. The peak relative T2 values in the tumors detected by the OSPIO- or WSPIO-loaded contrast agents were reduced by 10.12% and 11.40%, respectively. The relative T2 values in the WSPIO- and OSPIO-loaded polymeric nanovesicle groups were more pronounced than the relative T2 value in the WSPIO group (P<0.05), but there was no significant difference in the T2 value between the OSPIO- and WSPIO-loaded vesicle groups (P＞0.05). The greatest T2 value decreases in the liver in the WSPIO, OSPIO-loaded and WSPIO-loaded vesicle groups were 32.85%, 52.77% and 56.89%, respectively. The decrease in the T2 values was more pronounced in the WSPIO- and OSPIO-loaded nanovesicle groups than in the WSPIO group (P<0.05) and was more apparent in the WSPIO-loaded nanovesicle group than in the OSPIO-loaded nanovesicle group (P<0.05). SPIO-loaded polymeric nanovesicles generate significant T2WI signal intensity decreases in vivo and are anticipated to be used as novel and effective contrast agents for tumor imaging.

Prostate cancer targeted multifunctionalized graphene oxide for magnetic resonance imaging and drug delivery

Dendrimers capped with amino groups (DEN) are grafted to graphene oxide (GO) nanosheets for subsequent functionalization of GO with gadolinium diethylene triamine pentaacetate (Gd-DTPA) and prostate stem cell antigen (PSCA) monoclonal antibody (mAb). The as-prepared GO-DEN(Gd-DTPA)-mAb exhibits very low cytotoxicity, negligible hemolytic activity, and no perceptible toxic effects in mice. GO-DEN(Gd-DTPA)-mAb can specifically target PSCA over-expressed cancer cells to give a significant T1-weighted contrast enhancement effect. The in vivo magnetic resonance imaging results indicate that GO-DEN(Gd-DTPA)-mAb can be used as a targeted contrast agent for prostate tumor imaging. GO-DEN(Gd-DTPA)-mAb can be efficiently loaded with doxorubicin hydrochloride (DOX), and the resulting GO-DEN(Gd-DTPA)-mAb/DOX exhibits enhanced cytotoxicity to PC-3 cells due to good targeting performance. By following the PC-3 tumor growth in mouse model after intravenous administration of GO-DEN(Gd-DTPA)-mAb/DOX, it is demonstrated that GO-DEN(Gd-DTPA)-mAb can targetedly deliver anticancer drugs to malignant prostate tumors and inhibit tumor growth.

Review on near-infrared heptamethine cyanine dyes as theranostic agents for tumor imaging, targeting, and photodynamic therapy.

A class of near-infrared fluorescence (NIRF) heptamethine cyanine dyes that are taken up and accumulated specifically in cancer cells without chemical conjugation have recently emerged as promising tools for tumor imaging and targeting. In addition to their fluorescence and nuclear imaging-based tumor-imaging properties, these dyes can be developed as drug carriers to safely deliver chemotherapy drugs to tumors. They can also be used as effective agents for photodynamic therapy with remarkable tumoricidal activity via photodependent cytotoxic activity. The preferential uptake of dyes into cancer but not normal cells is co-operatively mediated by the prevailing activation of a group of organic anion-transporting polypeptides on cancer cell membranes, as well as tumor hypoxia and increased mitochondrial membrane potential in cancer cells. Such mechanistic explorations have greatly advanced the current application and future development of NIRF dyes and their derivatives as anticancer theranostic agents. This review summarizes current knowledge and emerging advances in NIRF dyes, including molecular characterization, photophysical properties, multimodal development and uptake mechanisms, and their growing potential for preclinical and clinical use.

Synthesis and Biological Evaluation of Novel (99m)Tc(CO)₃-Labeled Thymidine Analogs as Potential Probes for Tumor Proliferation Imaging.

Achieving a 99mTc labeled thymidine radiotracer for single photon emission tomography (SPECT) is considered to be of interest. In this study, four novel thymidine analogs, 6a, 6b, 6c and 6d, were successfully synthesized via “click reaction” route and then radiolabeled using a [99mTc(CO)3]+ core to prepare the corresponding 99mTc(CO)3 complexes in high yields. These complexes were hydrophilic and had good in vitro stability. Biodistribution of these complexes in mice bearing S180 tumors showed that all of them exhibited accumulation in the tumors, suggesting that they would be potential tumor imaging agents.

Nuclear imaging potential and in vitro photodynamic activity of symmetrical and asymmetrical zinc phthalocyanines.

Photodynamic therapy (PDT) is based on exposing a light-sensitive material that has been localized in target tissues with visible light. In the current study, symmetric Zn(II) octaoctadodecylphthalocyanine (1) and the asymmetrically substituted hydroxyhexyloxy derivative (2) were examined as a multifunctional agent for tumour nuclear imaging and for PDT potential. Zn(II)Pc 1 and Zn(II)Pc 2 were radiolabelled with (131) I using an iodogen method with high efficiency (93.5 ± 3.5% and 93.0 ± 2.8%, respectively) under the optimum conditions. Biodistribution study results showed that radiolabelled Zn(II)Pc 1 had a high uptake in the large intestine and unchanging uptake in the ovary. However, radiolabelled Zn(II)Pc 2 uptake was statically significant in the large intestine, pancreas, ovary and lung. For the PDT studies, EMT6/P (mouse mammary cell line) and HeLa (cervical adenocarcinoma cell line) with Zn(II)Pc 1 and Zn(II)Pc 2 were exposed to red light (650 nm) at 10-30 J/cm(2) . Zn(II)Pc 1 and Zn(II)Pc 2 had a good PDT efficacy in the EMT6/P cell line. In conclusion, radiolabelled Zn(II)Pc 1 might be a promising imaging agent for pancreas, ovary and colon tumours. However, the radiolabelled Zn(II)Pc 2 might be a promising nuclear imaging and PDT agent for colon, lung, pancreas and ovary tumours.

Microscopic validation of whole mouse micro-metastatic tumor imaging agents using cryo-imaging and sliding organ image registration.

We created a metastasis imaging, analysis platform consisting of software and multi-spectral cryo-imaging system suitable for evaluating emerging imaging agents targeting micro-metastatic tumor. We analyzed CREKA-Gd in MRI, followed by cryo-imaging which repeatedly sectioned and tiled microscope images of the tissue block face, providing anatomical bright field and molecular fluorescence, enabling 3D microscopic imaging of the entire mouse with single metastatic cell sensitivity. To register MRI volumes to the cryo bright field reference, we used our standard mutual information, non-rigid registration which proceeded: preprocess → affine → B-spline non-rigid 3D registration. In this report, we created two modified approaches: mask where we registered locally over a smaller rectangular solid, and sliding organ. Briefly, in sliding organ, we segmented the organ, registered the organ and body volumes separately and combined results. Though sliding organ required manual annotation, it provided the best result as a standard to measure other registration methods. Regularization parameters for standard and mask methods were optimized in a grid search. Evaluations consisted of DICE, and visual scoring of a checkerboard display. Standard had accuracy of 2 voxels in all regions except near the kidney, where there were 5 voxels sliding. After mask and sliding organ correction, kidneys sliding were within 2 voxels, and Dice overlap increased 4%-10% in mask compared to standard. Mask generated comparable results with sliding organ and allowed a semi-automatic process.

Tc-99m Glu-Cys-Gly-His-Gly-Lys (ECG-HGK), a novel Tc-99m labeled hexapeptide for molecular tumor imaging.

Domain 5 of kinin-free high molecular weight kininogen inhibits the adhesion of many tumor cell lines, and it has been reported that the histidine-glycine-lysine (HGK)-rich region might be responsible for inhibition of cell adhesion. The authors developed HGK-containing hexapeptide, glutamic acid-cysteine-glycine (ECG)-HGK, and evaluated the utility of Tc-99m ECG-HGK for tumor imaging. Hexapeptide, ECG-HGK was synthesized using Fmoc solid-phase peptide synthesis. Radiolabeling efficiency was evaluated. The uptake of Tc-99m ECG-HGK within HT-1080 cells was evaluated in vitro. In HT-1080 tumor-bearing mice, gamma imaging and biodistribution studies were performed. The complexes Tc-99m ECG-HGK was prepared in high yield. The uptake of Tc-99m ECG-HGK within the HT-1080 tumor cells had been demonstrated by in vitro studies. The gamma camera imaging in the murine model showed that Tc-99m ECG-HGK was accumulated substantially in the HT-1080 tumor (tumor-to-muscle ratio = 5.7 ± 1.4 at 4 h), and the tumoral uptake was blocked by the co-injection of excess HGK (tumor-to-muscle ratio = 2.8 ± 0.6 at 4 h). In the present study, Tc-99m ECG-HGK was developed as a new tumor imaging agents. Our in vitro and in vivo studies revealed specific function of Tc-99m ECG-HGK for tumor imaging.

Folate receptor targeted drug delivery- from the bench to the bedside

Targeted drug delivery is a promising strategy for improving tumor therapy. Folate receptor (FR) is an established ovarian cancer marker that is also frequently found to be overexpressed in other major epithelial tumors. Meanwhile, functional FR−β is expressed in myeloid leukemias and in inflammatory macrophages, including tumor-associated macrophages. FR based tumor targeted drug delivery has been a very active area of research and recent advancement of this technology towards clinical translation is highly significant. FR targeting can be achieved via anti-FR antibody or by folate conjugation, each with distinctive advantages and pitfalls. Several monoclonal antibodies directed against FR−α have been developed. In addition, a large number of imaging agents, drug molecules, and drug carriers have been conjugated to folate for targeting the FR, mostly for targeting FR−α found on the surface of epithelial tumor cells. Only recently, however, have FR-targeted agents moved into Phase III clinical trials, exemplified by the monoclonal antibody farletuzumab and the low molecular weight folate conjugates, folate-99mTc (EC20) and folate-desacetylvinblastinehydrazide (EC145), representing each of the two competing strategies for targeting the FR. This review will focus on the activities related to clinical translation of FR-targeted agents. The reader will gain a better understanding of the landscape of clinical translation of this exciting technology and key findings in the clinical trials. The anticipated approval of these agents and the ongoing clinical development of several other folate conjugates should usher in a new era of clinical translation and validation of FR-targeted imaging and therapeutic agents for tumor imaging and therapy.

Theranostic Application of Mixed Gold and Superparamagnetic Iron Oxide Nanoparticle Micelles in Glioblastoma Multiforme.

The treatment of glioblastoma multiforme, the most prevalent and lethal form of brain cancer in humans, has been limited in part by poor delivery of drugs through the blood-brain barrier and by unclear delineation of the extent of infiltrating tumor margins. Nanoparticles, which selectively accumulate in tumor tissue due to their leaky vasculature and the enhanced permeability and retention effect, have shown promise as both therapeutic and diagnostic agents for brain tumors. In particular, superparamagnetic iron oxide nanoparticles (SPIONs) have been leveraged as T2-weighted MRI contrast agents for tumor detection and imaging; and gold nanoparticles (AuNP) have been demonstrated as radiosensitizers capable of propagating electron and free radical-induced radiation damage to tumor cells. In this study, we investigated the potential applications of novel gold and SPION-loaded micelles (GSMs) coated by polyethylene glycol-polycaprolactone (PEG-PCL) polymer. By quantifying gh2ax DNA damage foci in glioblastoma cell lines, we tested the radiosensitizing efficacy of these GSMs, and found that GSM administration in conjunction with radiation therapy (RT) led to ~2-fold increase in density of double-stranded DNA breaks. For imaging, we used GSMs as a contrast agent for both computed tomography (CT) and magnetic resonance imaging (MRI) studies of stereotactically implanted GBM tumors in a mouse model, and found that MRI but not CT was sufficiently sensitive to detect and delineate tumor borders after administration and accumulation of GSMs. These results suggest that with further development and testing, GSMs may potentially be integrated into both imaging and treatment of brain tumors, serving a theranostic purpose as both an MRI-based contrast agent and a radiosensitizer.

Evaluation of 18F-labeled icotinib derivatives as potential PET agents for tumor imaging

In this study, three 18F-labeled crown ether fused anilinoquinazoline derivatives ([18F]11a–c) were synthesized and evaluated as potential tumor imaging probes. The biodistribution results of [18F]11b were good. Compared with [18F]-fludeoxyglucose and l-[18F]-fluoroethyltyrosine in the same animal model, [18F]11b had better tumor/brain, tumor/muscle, and tumor/blood uptake ratios. Overall, these results suggest that [18F]11b is promising as a tumor imaging agent for positron emission tomography.

Evaluation of (188)Re-labeled NGR-VEGI protein for radioimaging and radiotherapy in mice bearing human fibrosarcoma HT-1080 xenografts.

Vascular endothelial growth inhibitor (VEGI) is an anti-angiogenic protein, which includes three isoforms: VEGI-174, VEGI-192, and VEGI-251. The NGR (asparagine-glycine-arginine)-containing peptides can specifically bind to CD13 (Aminopeptidase N) receptor which is overexpressed in angiogenic blood vessels and tumor cells. In this study, a novel NGR-VEGI fusion protein was prepared and labeled with (188)Re for radioimaging and radiotherapy in mice bearing human fibrosarcoma HT-1080 xenografts. Single photon emission computerized tomography (SPECT) imaging results revealed that (188)Re-NGR-VEGI exhibits good tumor-to-background contrast in CD13-positive HT-1080 tumor xenografts. The CD13 specificity of (188)Re-NGR-VEGI was further verified by significant reduction of tumor uptake in HT-1080 tumor xenografts with co-injection of the non-radiolabeled NGR-VEGI protein. The biodistribution results demonstrated good tumor-to-muscle ratio (4.98 ± 0.25) of (188)Re-NGR-VEGI at 24h, which is consistent with the results from SPECT imaging. For radiotherapy, 18.5MBq of (188)Re-NGR-VEGI showed excellent tumor inhibition effect in HT-1080 tumor xenografts with no observable toxicity, which was confirmed by the tumor size change and hematoxylin and eosin (H&E) staining of major mouse organs. In conclusion, these data demonstrated that (188)Re-NGR-VEGI has the potential as a theranostic agent for CD13-targeted tumor imaging and therapy.

Tumor Targeting and Pharmacokinetics of a Near-Infrared Fluorescent-Labeled δ-Opioid Receptor Antagonist Agent, Dmt-Tic-Cy5.

Fluorescence molecular imaging can be employed for the development of novel cancer targeting agents. Herein, we investigated the pharmacokinetics (PK) and cellular uptake of Dmt-Tic-Cy5, a delta-opioid receptor (δOR) antagonist-fluorescent dye conjugate, as a tumor-targeting molecular imaging agent. δOR expression is observed normally in the CNS, and pathologically in some tumors, including lung liver and breast cancers. In vitro, in vivo, and ex vivo experiments were conducted to image and quantify the fluorescence signal associated with Dmt-Tic-Cy5 over time using in vitro and intravital fluorescence microscopy and small animal fluorescence imaging of tumor-bearing mice. We observed specific retention of Dmt-Tic-Cy5 in tumors with maximum uptake in δOR-expressing positive tumors at 3 h and observable persistence for >96 h; clearance from δOR nonexpressing negative tumors by 6 h; and systemic clearance from normal organs by 24 h. Live-cell and intravital fluorescence microscopy demonstrated that Dmt-Tic-Cy5 had sustained cell-surface binding lasting at least 24 h with gradual internalization over the initial 6 h following administration. Dmt-Tic-Cy5 is a δOR-targeted agent that exhibits long-lasting and specific signal in δOR-expressing tumors, is rapidly cleared from systemic circulation, and is not retained in non-δOR-expressing tissues. Hence, Dmt-Tic-Cy5 has potential as a fluorescent tumor imaging agent.

Enhancing the circulating half-life and the antitumor effects of a tumor-selective cytotoxic peptide by exploiting endogenous serum albumin as a drug carrier

The elevated expression of bombesin receptors in many of the deadliest cancers has attracted special interest in developing bombesin-directed agents for tumor imaging and therapy. Previously, we constructed the chimeric peptide BB28 by fusing bombesin to a mitochondria-disrupting peptide. BB28 selectively induced the apoptosis of various tumor cells in vitro and showed promising in vivo antitumor effects. In general, a short circulating half-life limits the in vivo effect of peptides. To prolong the half-life of BB28, here, we generated the novel peptide ABB28 by fusing an albumin-binding domain (ABD) to the N-terminus of BB28. ABB28 exhibited much higher binding affinity for albumin than BB28, and this modification extended the peptide half-life from several minutes to 2h. Optical imaging revealed that ABB28 accumulated in xenografted tumors within 1h post-injection and persisted at an evident level for up to 24h. ABB28 exerted stronger tumor-suppressive effects than BB28. Significant differences in the tumor volumes (P<0.001) and the tumor weights (P=0.002) were observed between ABB28- and BB28-treated mice. Moreover, ABB28 exhibited tumor suppression comparable to that of PEGylated 5K-BB28 in vivo. These results suggest that half-life extension via ABD fusion represents a useful strategy for optimizing bombesin-directed pharmaceuticals for cancer-targeted therapy.

177Lu-Dendrimer Conjugated to Folate and Bombesin with Gold Nanoparticles in the Dendritic Cavity: A Potential Theranostic Radiopharmaceutical

177Lu-labeled nanoparticles conjugated to biomolecules have been proposed as a new class of theranostic radiopharmaceuticals. The aim of this research was to synthesize 177Lu-dendrimer(PAMAM-G4)-folate-bombesin with gold nanoparticles (AuNPs) in the dendritic cavity and to evaluate the radiopharmaceutical potential for targeted radiotherapy and the simultaneous detection of folate receptors (FRs) and gastrin-releasing peptide receptors (GRPRs) overexpressed in breast cancer cells. p-SCN-Benzyl-DOTA was conjugated in aqueous-basic medium to the dendrimer. The carboxylate groups of Lys1Lys3(DOTA)-bombesin and folic acid were activated with HATU and also conjugated to the dendrimer. The conjugate was mixed with 1% HAuCl4 followed by the addition of NaBH4 and purified by ultrafiltration. Elemental analysis (EDS), particle size distribution (DLS), TEM analysis, UV-Vis, and infrared and fluorescence spectroscopies were performed. The conjugate was radiolabeled using 177LuCl3 or 68GaCl3 and analyzed by radio-HPLC. Studies confirmed the dendrimer functionalization with high radiochemical purity (&gt;95%). Fluorescence results demonstrated that the presence of AuNPs in the dendritic cavity confers useful photophysical properties to the radiopharmaceutical for optical imaging. Preliminary binding studies in T47D breast cancer cells showed a specific cell uptake (41.15±2.72%). 177Lu-dendrimer(AuNP)-folate-bombesin may be useful as an optical and nuclear imaging agent for breast tumors overexpressing GRPR and FRs, as well as for targeted radiotherapy.

Synthesis and biodistribution of novel 99mTcN complexes of glucose dithiocarbamate as potential probes for tumor imaging

99mTcN-3b can be prepared from a kit without the need for purification and would be a promising tumor imaging agent.

Biometabolic Distribution of 99mTc-3PRGD2 and Its Potential Value in Monitoring Chemotherapeutic Effects.

Previous studies have reported that 99mTc-3PRGD2 is an excellent tumor imaging agent that showed a good correlation with integrin αvβ3, a main factor of tumor-induced angiogenesis. In this study, we investigated the biometabolic distribution characteristics of 99mTc-3PRGD2 with a continuous dynamic acquisition mode to explore the potential value of 99mTc-3PRGD2 in monitoring chemotherapeutic effects in VX2 tumor models. Eighteen rabbits with 27 implanted VX2 squamous cell tumors were randomly divided into a nontreated control group (NTG, n = 8; 12 tumors) and a treatment group (TG, n = 10; 15 tumors). 99mTc-3PRGD2 imaging was performed prior to cisplatin injection and repeated on days 0, 1, 7, and 14 postinjection. Continuous dynamic scanning up to 30 minutes; static imaging at 0.5 hours, 1 hour, and 3 hours; and single-photon emission computed tomography/computed tomography (SPECT/CT)-integrated imaging at 3 hours post-99mTc-3PRGD2 injection were performed. The peak time (time to reach peak in dynamic curve), tumor to normal (T/N) ratios, and their change rates relative to pretherapy were calculated. Autoradiography, hematoxylin-eosin (H&E) staining, and CD31 and integrin αv immunohistochemical staining were examined. VX2 tumors were clearly visualized at 3 hours post-99mTc-3PRGD2 injection. Tumors in the TG shrank significantly on day 7 after cisplatin administration (p < .05). The half-life (t1/2) of the radiotracer in heart, liver, and tumor in the NTG were 3.43 ± 0.94 minutes, 13.41 ± 9.17 minutes, and 70.83 ± 33.37 minutes, respectively. The peak time was delayed in the TG immediately and continuously after cisplatin administration compared to the peak time in the NTG. The T/N values and their change rates decreased significantly in the TG compared to the NTG after therapy (p < .05). The immunostained areas were significantly decreased in the TG (p < .05) compared to the NTG. 99mTc-3PRGD2 was an excellent imaging agent for demonstrating tumor angiogenesis. The peak time, T/N values, and their change rates were sensitive parameters to monitor early chemotherapeutic effects. Due to the specific target mechanism and the cost-effective value of 99mTc-3PRGD2, 99mTc-3PRGD2 SPECT imaging may have potential in detecting the therapeutic effects of anticancer therapy.

Preliminary evaluation of novel 18F-AlF-NOTA-IF7 as a tumor imaging agent

Annexin 1 (Anxa1) is a highly specific surface marker of tumor vasculature. A carbohydrate ligand-mimicking 7-mer peptide, IFLLWQR (Ile-Phe-Leu–Leu-Trp-Gln-Arg, IF7) can target Anxa1 in tumor vasculature. IF7 was first conjugated with a macrocyclic chelator, 1, 4, 7- triazacyclononane-1, 4, 7- triacetic acid (NOTA), and the resulting bioconjugate NOTA-IF7 was then radiofluorinated via Al18F intermediate to synthesize 18F-AlF-NOTA-IF7. MicroPET studies demonstrated that 18F-AlF-NOTA-IF7 had good uptake in tumor. 18F-AlF-NOTA-IF7 is a promising radiopharmaceutical in tumor imaging. The favorable characterizations of 18F-AlF-NOTA-IF7 such as convenient synthesis, specific Anxa1 targeting and moderate tumor uptake make it possible for imaging of cancers.

Preclinical evaluation of 2-amino-2-[11C]methyl-butanoic acid as a potential tumor-imaging agent in a mouse model.

C-labeled 2-amino-2-methyl-butanoic acid (Iva) was previously reported to provide high tumor uptake; however, the pharmacokinetic properties of C-labeled Iva have not been characterized. In the present study, we evaluated the potential of [C]Iva as a PET probe for tumor imaging. [C]Iva was incubated in mouse serum for 60 min at 37°C and then analyzed by high-performance liquid chromatography and thin-layer chromatography. In-vitro cellular uptake of [C]Iva was determined in PBS and sodium-free buffer at 37°C using SY human small-cell lung cancer cells. The effects of inhibitors of amino acid transporters on [C]Iva uptake were also determined in PBS. In-vivo distribution and dynamic PET studies were conducted in SY tumor-bearing mice. [C]Iva was stable in mouse serum in vitro for 60 min. The cellular uptake of [C]Iva was linearly increased for 20 min in both PBS and sodium-free buffer and almost completely inhibited by an inhibitor of system L amino acid transporters and another of LAT1, a transporter of system L. In-vivo distribution and dynamic PET studies showed that [C]Iva was highly accumulated in tumor, but not in normal tissues, except for the pancreas and kidneys. The [C]Iva uptake ratio of tumor to several normal tissues, such as the lung, muscle, and brain, was high. [C]Iva was stable in mouse serum and transported through system L amino acid transporters including LAT1, which is highly expressed in several tumors. [C]Iva is a promising PET probe for noninvasive tumor imaging.

Radioiodination and biological evaluation of Cladribine as potential agent for tumor imaging and therapy

Abstract Cladribine, a purine analogue antimetabolite, was radioiodinated with 125I via direct electrophilic substitution reaction. The maximum radiochemical yield (92.5 ± 0.8%) was obtained when the reaction was done at ambient temperature for 30 min using 100 μg of Cladribine and 10 μg N-chlorosuccinamide (NCS) in 150 μL of 0.2 M phosphate buffer, pH 7. In vitro stability studies of HPLC purified 125I-Cladribine sample dissolved in 0.5 ml of 0.2 M phosphate buffer pH 7 at ambient temperature showed that 125I-Cladribine is stable up to 12 h post labeling. Biodistribution results revealed excretion of 125I-Cladribine mainly by kidneys. The uptake of 125I-Cladribine in the induced Ehrlich Ascites Carcinoma was 2.8 ± 0.4 %ID/g at 1 h post injection with maximum tumor/muscle ratio of 5.5. The good uptake of 125I-Cladribine confirms the molecular docking studies results which indicate that iodinated Cladribine binds with polymerase enzyme with a good –CDOCKER energy. As a result, radioiodinated Cladribine may be used as a valuable agent for tumor diagnosis and therapy.