Tumor Imaging Agent Research Articles

Exploiting Single Atom Iron Centers in a Porphyrin-like MOF for Efficient Cancer Phototherapy.

In recent years, single-atom catalysts (SACs) have attracted enormous attention due their effectiveness in promoting a variety of catalytic reactions. However, the ability of SACs to enhance cancer phototherapies has received little attention to date. Herein, we synthesized a metal organic framework (MOF) rich in porphyrin-like single atom Fe(III) centers (denoted herein as porphyrin-MOF or P-MOF) and then evaluated the performance of the P-MOF for cancer treatment by photodynamic therapy (PDT) and photothermal therapy (PTT) under NIR (808 nm) irradiation, as well as photoacoustic imaging (PAI) of tumors. On acccount of the abundance of single atom Fe(III) centers, the P-MOF material demonstrated excellent performance for modulation of the hypoxic tumor microenvironment of Hela cell tumors in mice, while also demonstrating good properties as a photoacoustic imaging (PAI) agent. Density functional theory (DFT) calculations were used to elucidate the superior performance of P-MOF in these applications relative to Fe2O3 (a Fe(III) reference compound). The calculations revealed that the narrow band gap energy of P-MOF (1.31 eV) enabled strong absorption of NIR photons, thereby inducing nonradiative transitions that converted incident light into heat to promote PTT. Further, a facile change of the spin state of the single atom Fe(III) centers in P-MOF under NIR irradiation transformed coordinated triplet oxygen (3O2) to singlet oxygen (1O2), benefiting PDT. This work demonstrates the great future potential of both SACs and MOFs as multifunctional agents for cancer treatment and tumor imaging.

18F-Fluciclovine (18F-FACBC) PET imaging of recurrent brain tumors

PurposeThe aim of our study was to investigate the efficacy of 18F-Fluciclovine brain PET imaging in recurrent gliomas, and to compare the utility of these images to that of contrast enhanced magnetic resonance imaging (MRI) and to [11C-methyl]-L-methionine (11C-Methionine) PET imaging. We also sought to gain insight into the factors affecting the uptake of 18F-FACBC in both tumors and normal brain, and specifically to evaluate how the uptake in these tissues varied over an extended period of time post injection.MethodsTwenty-seven patients with recurrent or progressive primary brain tumor (based on clinical and MRI/CT data) were studied using dynamic 18F-Fluciclovine brain imaging for up to 4 h. Of these, 16 patients also had 11C-Methionine brain scans. Visual findings, semi-quantitative analyses and pharmacokinetic modeling of a subset of the 18F-Fluciclovine images was conducted. The information derived from these analyses were compared to data from 11C-Methionine and to contrast-enhanced MRI.Results18F-Fluciclovine was positive for all 27 patients, whereas contrast MRI was indeterminate for three patients. Tumor 18F-Fluciclovine SUVmax ranged from 1.5 to 10.5 (average: 4.5 ± 2.3), while 11C-Methionine’s tumor SUVmax ranged from 2.2 to 10.2 (average: 5.0 ± 2.2). Image contrast was higher with 18F-Fluciclovine compared to 11C-Methionine (p < 0.0001). This was due to 18F-Fluciclovine’s lower background in normal brain tissue (0.5 ± 0.2 compared to 1.3 ± 0.4 for 11C-Methionine). 18F-Fluciclovine uptake in both normal brain and tumors was well described by a simple one-compartment (three-parameter: Vb,k1,k2) model. Normal brain was found to approach transient equilibrium with a half-time that varied greatly, ranging from 1.5 to 8.3 h (mean 2.7 ± 2.3 h), and achieving a consistent final distribution volume averaging 1.4 ± 0.2 ml/cc. Tumors equilibrated more rapidly (t1/2ranging from 4 to 148 min, average 57 ± 51 min), with an average distribution volume of 3.2 ± 1.1 ml/cc. A qualitative comparison showed that the rate of normal brain uptake of 11C-Methionine was much faster than that of 18F-Fluciclovine.ConclusionTumor uptake of 18F-Fluciclovine correlated well with the established brain tumor imaging agent 11C-Methionine but provided significantly higher image contrast. 18F-Fluciclovine may be particularly useful when the contrast MRI is non-diagnostic. Based on the data gathered, we were unable to determine whether Fluciclovine uptake was due solely to recurrent tumor or if inflammation or other processes also contributed.

Camouflaging bacteria by wrapping with cell membranes

Bacteria have been extensively utilized for bioimaging, diagnosis and therapy given their unique characteristics including genetic manipulation, rapid proliferation and disease site targeting specificity. However, clinical translation of bacteria for these applications has been largely restricted by their unavoidable side effects and low treatment efficacies. Engineered bacteria for biomedical applications ideally need to generate only a low inflammatory response, show slow elimination by macrophages, low accumulation in normal organs, and almost unchanged inherent bioactivities. Here we describe a set of stealth bacteria, cell membrane coated bacteria (CMCB), meeting these requirement. Our findings are supported by evaluation in multiple mice models and ultimately demonstrate the potential of CMCB to serve as efficient tumor imaging agents. Stealth bacteria wrapped up with cell membranes have the potential for a myriad of bacterial-mediated biomedical applications.

Radiolabeling, Preparation, and Bioevaluation of 99mTc-Azathioprine as a Potential Targeting Agent for Solid Tumor Imaging

Azathioprine, an antitumor agent, was labeled with 99mTc using stannous chloride dihydrate as a reducing agent. Factors such as the amounts of the reducing agent and substrate, pH, and reaction temperature and time were systematically studied to determine the optimum conditions, under which the 95% radiochemical yield was achieved. Biodistribution studies demonstrate the suitability of 99mTc-azathioprine as a novel tracer for tumor imaging. It shows high selectivity to high-replicating solid tumors.

Novel 18F-Labeled α-Methyl-Phenylalanine Derivative with High Tumor Accumulation and Ideal Pharmacokinetics for Tumor-Specific Imaging.

Positron emission tomography (PET) imaging with 18F-labeled α-methyl-substituted amino acids exerts significant influence on differential diagnosis of malignant tumors and tumor-like lesions. Exclusive uptake via L-type amino acid transporter 1 (LAT1), a tumor-specific transporter, accounts for their excellent tumor specificity and low background accumulation. However, further refinement and optimization in their tumor accumulation and pharmacokinetics are sorely needed. To address these issues, we newly designed 18F-labeled α-methyl-phenylalanine (18F-FAMP) regioisomers (2-, 3-, or 4-18F-FAMP) and stereoisomers (L- or D-form), and we comprehensively evaluated their potential as tumor-imaging agents. 18F-FAMPs were prepared from α-methyl phenylalanine by electrophilic radiofluorination and purified by reversed-phase HPLC. In biodistribution studies on normal mice, L-2-18F-FAMP and the three D-18F-FAMPs showed faster blood clearance and lower renal accumulation than L-3-18F-FAMP or L-4-18F-FAMP. In LS180 human colorectal cancer cell line xenograft mice, L-2-18F-FAMP exhibited significantly higher tumor accumulation than the D-18F-FAMPs or a clinically relevant tracer, L-3-18F-α-methyl-tyrosine (18F-FAMT) (p < 0.05). The renal accumulation levels of L-2-18F-FAMP were significantly lower than that of 18F-FAMT (p < 0.01). LAT-1 specificity of L-2-18F-FAMP was validated in the cellular uptake studies. The PET imaging with L-2-18F-FAMP clearly visualized the tumor as early as 1 h after injection, and the high tumor accumulation level was retained for 3 h. These findings suggest that L-2-18F-FAMP constitutes a potential PET tracer for tumor-specific imaging.

Peripheral ganglia in healthy rats as target structures for the evaluation of PSMA imaging agents

BackgroundThe recent implementation of PET with prostate specific membrane antigen (PSMA)-specific radiotracers into the clinical practice has resulted in the significant improvement of accuracy in the detection of prostate carcinoma (PCa). PSMA-expression in ganglia has been regarded as an important pitfall in prostate carcinoma-PET diagnostics but has not found any practical use for diagnosis or therapy.MethodsWe explored this phenomenon and demonstrated the applicability of peripheral ganglia in healthy rats as surrogates for small PSMA positive lesions for the preclinical evaluation of diagnostic PCa PET probes. Healthy rats were measured with PET/CT using the tracers [18F]DCFPyL, [Al18F]PSMA-11 and [68Ga]PSMA-11. Sections of ganglia were stained with an anti-PSMA antibody. [18F]DCFPyL uptake in ganglia was compared to that in LNCaP tumor xenografts in mice.ResultsWhereas [18F]DCFPyL and [68Ga]PSMA-11 were stable in vivo and accumulated in peripheral ganglia, [Al18F]PSMA-11 suffered from fast in vivo deflourination resulting in high bone uptake. Ganglionic PSMA expression was confirmed by immunohistochemistry. [18F]DCFPyL uptake and signal-to-noise ratio in the superior cervical ganglion was not significantly different from LNCaP xenografts.ConclusionsOur results demonstrated the non-inferiority of the novel model compared to conventionally used tumor xenografts in immune compromised rodents with regard to reproducibility and stability of the PSMA signal. Furthermore, the model involves less expense and efforts while it is permanently available and avoids tumor-growth associated animal morbidity and distress. To the best of our knowledge, this is the first tumor-free model suitable for the in vivo evaluation of tumor imaging agents.

Subphthalocyanine as a fluorescence imaging agent for breast tumor

Tri-tert-butyl-carboxyl subphthalocyanine (SubPc) was synthesized and evaluated as a fluorescence agent. Fluorescence imaging for breast tumor in vivo was performed using nude mice as models. Results indicate high uptake in tumor at 20 h. Tumor-non tumor ratio was determined as 2.25. The imaging results demonstrate the potential of this fluorescence-imaging agent in the diagnosis of breast tumor. In the future, subphthalocyanine is also developing as a dual functional, which is fluorescence imaging and as a photodynamic therapeutic agent for the treatment and diagnosis of cancer.

Amphiphilic Gemini Iridium(III) Complex as a Mitochondria-Targeted Theranostic Agent for Tumor Imaging and Photodynamic Therapy.

Clinical diagnostics and therapeutics of tumors are significantly benefitted by the development of multifunctional theranostic agents, which integrate tumor targeting, imaging, and therapeutics. However, the integration of imaging and therapy functionalities to a unimolecular framework remains a great challenge. Herein, a family of amphiphilic gemini iridium(III) complexes (GIC), Ir1-Ir6, are synthesized and characterized. The presence of quaternary ammonium (QA) groups endows GIC with adjustable water solubility and excellent self-assembly properties. Spectroscopic and computational results reveal that introducing QA groups into cyclometalating ligands (ĈN ligands) can overcome the drawback of aggregation-caused emission quenching and ensure Ir1-Ir3 with high emission intensity and excellent singlet oxygen (1O2) generation ability in aqueous media. Cell-based assays indicate that Ir3 shows higher cellular uptake efficiency and localizes specifically in the mitochondria, as well as exhibits outstanding photostability and an impressive phototoxicity index with satisfactory performance in mitochondria-targeted imaging and photodynamic therapy (PDT) of tumor cells. Furthermore, in vivo studies further prove that Ir3 possesses excellent antitumor activity and remarkably inhibits the growth of the HepG2 cells under PDT treatment. Consequently, this study presents a promising strategy for designing clinical application potential multifunctional iridium complex theranostic agents for mitochondria-targeted imaging and PDT in a single molecular framework.

Molecular Engineering of an Organic NIR-II Fluorophore with Aggregation-Induced Emission Characteristics for In Vivo Imaging.

Design and synthesis of new fluorophores with emission in the second near-infrared window (NIR-II, 1000-1700 nm) have fueled the advancement of in vivo fluorescence imaging. Organic NIR-II probes particularly attract tremendous attention due to excellent stability and biocompatibility, which facilitate clinical translation. However, reported organic NIR-II fluorescent agents often suffer from low quantum yield and complicated design. In this study, the acceptor unit of a known NIR-I aggregation-induced emission (AIE) luminogen (AIEgen) is molecularly engineered by varying a single atom from sulfur to selenium, leading to redshifted absorption and emission spectra. After formulation of the newly prepared AIEgen, the resultant AIE nanoparticles (referred as L897 NPs) have an emission tail extending to 1200 nm with a high quantum yield of 5.8%. Based on the L897 NPs, noninvasive vessel imaging and lymphatic imaging are achieved with high signal-to-background ratio and deep penetration. Furthermore, the L897 NPs can be used as good contrast agents for tumor imaging and image-guided surgery due to the high tumor/normal tissue ratio, which peaks at 9.0 ± 0.6. This work suggests a simple strategy for designing and manufacturing NIR-II AIEgens and demonstrates the potential of NIR-II AIEgens in vessel, lymphatic, and tumor imaging.

Evaluation of 5-[18F]fluoro-2ʹ-deoxycytidine as a tumor imaging agent: A comparison of [18F]FdUrd, [18F]FLT and [18F]FDG

One of the hallmarks of cancer is increased cell proliferation. Measurements of cell proliferation by estimation of DNA synthesis with several radiolabeled nucleosides have been tested to assess tumor growth. Deoxycytidine can be phosphorylated by deoxycytidine kinase (dCK) and is incorporated into DNA. This study evaluated a radiofluorinated deoxycytidine analog, 5-[18F]fluoro-2′-deoxycytidine ([18F]FdCyd), as a proliferation probe and compared it with 5-[18F]fluoro-2′-deoxyuridine ([18F]FdUrd), 3′-deoxy-3'-[18F]fluorothymidine ([18F]FLT), and [18F]fluorodeoxyglucose ([18F]FDG) in a tumor-bearing mouse model. [18F]FdCyd was synthesized from two precursors by direct electrophilic substitution. The serum stability and partition coefficient of [18F]FdCyd were evaluated in vitro. Positron emission topography (PET) imaging of Lewis lung carcinoma (LLC)-bearing mice with [18F]FdCyd, [18F]FdUrd, [18F]FLT, and [18F]FDG were evaluated. [18F]FdCyd was stable in mouse serum and normal saline for up to 4 h. With all radiotracers except [18F]FLT, PET can clearly delineate the tumor lesion. [18F]FdCyd and [18F]FdUrd showed high accumulation in the liver and kidney. The SUV and tumor-to-muscle (T/M) ratios derived from PET imaging of the radiotracers were [18F]FDG > [18F]FdCyd > [18F]FdUrd > [18F]FLT. Selective retention in tumors with a favorable tumor/muscle ratio makes [18F]FdCyd a protential candidate for further investigation as a proliferation imaging agent.

A C-Terminal Fragment of Chlorotoxin Retains Bioactivity and Inhibits Cell Migration.

Chlorotoxin was originally isolated from the venom of the Israeli scorpion Leiurus quinquestriatus, and has potential as a tumor imaging agent based on its selective binding to tumor cells. Several targets have been suggested for chlorotoxin including voltage-gated chloride channels, and it has been shown to have anti-angiogenic activity and inhibit cell migration. The structure of chlorotoxin is stabilized by four disulfide bonds and contains β-sheet and helical structure. Interestingly, the reduced form has previously been shown to inhibit cell migration to the same extent as the wild type, but structural analysis indicates that the reduced form of the peptide does not maintain the native secondary structure and appears unstructured in solution. This lack of structure suggests that a short stretch of amino acids might be responsible for the bioactivity. To explore this hypothesis, we have synthesized fragments of chlorotoxin without disulfide bonds. As expected for such small peptides, NMR analysis indicated that the peptides were unstructured in solution. However, the peptide corresponding to the eight C-terminal residues inhibited cell migration, in contrast to the other fragments. Our results suggest that the C-terminal region plays a critical role in the bioactivity of chlorotoxin.

Biological evaluation of histidine and tryptophan labeled with gallium-68 as potential tumor imaging agents

Radiolabeled with gallium-68 amino acids can be interesting and promising probes for tumor imaging using positron emission tomography (PET). Radiolabeled amino acids target the increased amino acid transport in cancer cells compared with normal tissues. In this study we labeled two amino acids histidine and tryptophan with 68Ga, investigated its biodistribution in Wistar rats with subcutaneously transplanted cholangioma RS-1 by gamma counting and compared them with 68GaCl3. The accumulation of 68Ga-histidine in tumor tissue increased approximately 6 fold from 0.11±0.04 %ID/g at 5 min post injection (p.i.) to 0.67±0.07 %ID/g at 3 h p.i. The amount of 68Ga-tryptophan in tumor was also risen 2.4 fold from 0.34±0.18 %ID/g to 0.80±0.06 %ID/g at 5 min and 3 h p.i., respectively. In contrast, the uptake of 68GaCl3 decreased throughout the study from 0.34±0.07 %ID/g to 0.13±0.04 %ID/g. The uptake and retention of 68Ga-histidine and 68Ga-tryptophan in non-target organs, except kidney and femur, were higher than those of 68GaCl3. In conclusion, the obtained results suggest that 68Ga-histidine and 68Ga-tryptophan could serve as potential new PET tracers for tumor imaging.

Synthesis of a Potential Tumor Imaging Agent by Oxidative Radioiodination of Aspirin and Its Preclinical Study

Aspirin, one of nonsteroidal anti-inflammatory analgesic drugs, was labeled with 125I with a labeling yield of 85.5% under the following conditions: pH 9, 100 mg of the substrate, 50 µg of Chloramine-T, 5–15 min, room temperature. The radiochemical yield of 125I-aspirin was determined by paper chromatography and electrophoresis, and the radiochemical purity was determined by HPLC.125I-aspirin was stable for at least 3 h. Biodistribution of 125I-aspirin in normal and tumor-bearing mice was studied. The uptake of 125I-aspirin in tumor sites makes it promising as a new radiopharmaceutical for tumor imaging.

Radiolabeled, folate-conjugated liposomes as tumor imaging agents: Formulation and in vitro evaluation

Cancer is the major burden of disease worldwide. The folate receptor, as a specific tumor target, is over-expressed in many types of cancer including ovarian carcinomas, breast, colon, renal, and lung tumors. Nuclear medicine hybrid imaging modalities, such as SPECT/CT, provide both metabolic and anatomic information. Therefore, specific contrast agents are essentially needed. Liposomes are favorable systems with many advantages. The aim of this study was to formulate liposomal imaging agents for molecular tumor imaging by SPECT or SPECT/CT and evaluate their efficacy. Nanosized, polyethyleneglycolated, folate-conjugated and unmodified, diethylenetriaminepentaacetic acid-phosphatidylethanolamine containing, neutral and positively charged liposomes were formulated and characterized by mean particle size, zeta potential, and quantitative determination of the phospholipids in the liposomes. The binding of the synthetized imaging agents to 4T1 breast tumor cells was evaluated by fluorescence microscopy and radioactivity counting. Folate-conjugated neutral and positively charged liposomes were found to be effective as tumor imaging agents exhibiting an almost 3-fold increased uptake and brighter fluorescence microscopy images than unmodified ones in in vitro experiments using 4T1 breast tumor cells. These results could be considered as an important step towards the development of folate-specific agents for tumor imaging by SPECT and SPECT/CT.

Fe3O4-ZIF-8 assemblies as pH and glutathione responsive T2-T1 switching magnetic resonance imaging contrast agent for sensitive tumor imaging in vivo.

A small Fe3O4 nanoparticles-based T1 contrast agent was assembled into a pH- and glutathione-responsive T2-T1 switching contrast agent, Fe3O4-ZIF-8. In vivo T1-weighted images of mice showed that Fe3O4-ZIF-8 displayed darkening contrast enhancement for liver sites, while darkening to brightening contrast enhancement at tumor sites, giving large inverse contrast for distinguishing the normal and tumor tissues.

Iron phosphide nanoparticles as a pH-responsive T 1 contrast agent for magnetic resonance tumor imaging.

In this work, the potential of FeP nanoparticles as a pH-responsive T1 contrast agent was investigated. The FeP nanoparticles have good biocompatibility and can significantly amplify T1 magnetic resonance signals in response to the acidic microenvironment of solid tumors, holding great promise in serving as an acid-activatable T1 contrast agent for tumor imaging.

Stearic Acid-Grafted Chitooligosaccharide Nanomicelle System with Biocleavable Gadolinium Chelates as a Multifunctional Agent for Tumor Imaging and Drug Delivery.

Theranostic nanoplatforms are promising approaches for diagnosis and treatment. Here, we report a drug-loaded nanomicelle system with biocleavable gadolinium (Gd) chelates as a multifunctional biodegradable agent for simultaneous magnetic resonance imaging (MRI) and drug delivery. Self-assembled nanomicelles based on stearic acid-grafted chitooligosaccharide were utilized as vehicles. Gd chelates, DTPA-Gds, were linked to the nanomicelles via redox-responsive disulfide bonds, and hydrophobic drugs were encapsulated in the micelle cores. MRI and cargo delivery were investigated in orthotopic pancreatic tumor-bearing mice. In vivo MRI demonstrated that the biodegradable agent was cleaved by endogenous thiols after intravenous injection, and the released DTPA-Gds were eliminated rapidly. At the same time, the agent resulted in a greater contrast enhancement of T1-weighted MR signal intensity at the tumor region than Magnevist®, and the tumor boundaries were clearly defined for at least 2h. In addition, the agent possessed high drug-loading and tumor-targeting capacities. Loading content and encapsulation efficiency of docetaxel were 3.2% and 99.4%, respectively. Compared with Taxotere®, the commercially available docetaxel injection, the docetaxel-loaded agent significantly increased the drug concentration in tumor tissue in vivo. The fabricated multifunctional agent may serve as a biodegradable nanoscale MRI contrast agent and as a drug delivery system for tumor diagnosis and treatment.

Radioiodination and biological distribution of a new s-triazine derivative for tumor uptake evaluation.

A newly synthesized s-triazine derivative 1,1',1″-(((1,3,5-triazine-2,4,6-triyl) tris (azanediyl)) tris (benzene-4,1-diyl))tris (ethan-1-one), (1), was synthesized as a part of an ongoing research for development of novel s-triazine-based radiopharmaceuticals. In-vitro cell viability assay against different human cancer cell lines showed very promising inhibitory activity of the synthesized compound. This finding encouraged the radioiodination of 1 to study the degree of its localization in tumor site for evaluating the possibility of its use as a tumor imaging agent. The biodistribution study showed good localization of the radioiodinated derivative 2 at tumor site following i.v. administration in solid tumor-bearing mice. Finally, in a trial to understand the mechanism of the anticancer effect exerted by 1, a target prediction study and a docking study were performed. The results of the first study showed that focal adhesion kinase is a possible target for compound 1 and the docking study confirmed successful binding of both compound 1 and its radioiodinated derivative 2 to the binding site of focal adhesion kinase. As a conclusion, the results of this study suggest that, compound 2 could be used as a potential agent for tumor imaging after preclinical trials.

Substrate-assisted enzymatic formation of lysinoalanine in duramycin.

Duramycin is a heavily post-translationally modified peptide that binds phosphatidylethanolamine. It has been investigated as an antibiotic, inhibitor of viral entry, therapeutic for cystic fibrosis, and tumor and vasculature imaging agent. Duramycin contains a β-hydroxylated Asp (Hya) and four macrocycles, including an essential lysinoalanine (Lal) crosslink. The mechanism of Lal formation is not known. We here show that Lal is installed stereospecifically by DurN via addition of Lys19 to a dehydroalanine. The structure of DurN reveals an unusual dimer with a new fold. Surprisingly, in the structure of duramycin bound to DurN, no residues of the enzyme are near the Lal crosslink. Instead, Hya15 of the substrate makes interactions with Lal, suggesting it acts as a base to deprotonate Lys19 during catalysis. Biochemical data suggest that DurN preorganizes the reactive conformation of the substrate, such that the Hya15 of the substrate can serve as the catalytic base for Lal formation.

Gadolinium(III)-based Polymeric Magnetic Resonance Imaging Agents for Tumor Imaging.

Contrast agents (CAs) are widely used to improve the signal-noise ratio in the magnetic resonance imaging (MRI) examinations. The majority of MRI CAs used in clinic are gadolinium( III) (Gd(III)) chelates with low molecular weight. Compared with these small-molecule CAs, Gd(III)-based polymeric magnetic resonance imaging agents (i.e. macromolecular contrast agents, mCAs), prepared by conjugating small-molecule Gd(III) chelates onto macromolecules, possess high relaxivity and relative long blood circulation time, which are favorable for MRI examinations. In last decades, increasing attention was paid to the design of mCAs with various structures, and further evaluation of the MRI performance both in vitro and in vivo. Herein, we focus on the recent progress of mCAs, including structures, properties and applications. Meanwhile, this review also highlights the emerging MRI mCAs with smart response and multi-function: tumor microenvironment- stimulated MRI, multi-mode imaging and MRI-based theranostics.