Tumor Imaging Agent Research Articles

Design, synthesis, and biological evaluation of F-18-labelled 2, 4-diaminopyrimidine-type FAK-targeted inhibitors as potential tumour imaging agents

As a type of intracellular nonreceptor tyrosine kinase, focal adhesion kinase (FAK) can be highly expressed in most types of tumours and is thus regarded as a promising antitumour target. In this study, a series of novel 2,4-diaminopyrimidine FAK-targeted inhibitors were designed, synthesized and characterized by 1H NMR, 13C HNMR, and HRMS spectra. These compounds, with an IC50 range of 5.0–205.1 nM, showed superior inhibitory activity against FAK. Two compounds, [18F]Q-2 and [18F]Q-4, with respective IC50 values of 5.0 nM and 21.6 nM, were labelled by 18F, accompanied by evaluation of their biodistributions. For [18F]Q-2, at 30 min post-injection, promising target-to-nontarget ratios were observed, associated with tumour/blood, tumour/muscle, and tumour/bone ratios of 1.17, 2.99 and 2.19, respectively. The results indicated that [18F]Q-2 is a potential PET tracer for tumour diagnosis.

Organelle-Partitioned Sugar-Rhodamine Diad for In Vivo Tumor Imaging.

Current tumor imaging agents are often limited by their liability to dissipate from tumor tissues. As cell sugar sorting enables exogenous sugars to be delivered into predetermined subcellular locations, we synthesized sialic acid (Sia) derivatives with rhodamine-X conjugated at C-9 (ROXSia), which hitchhikes cell sialic acid sorting to target tumor cell lysosomes, exhibiting pH-independent long-term probe retention in lysosomes. ROXSia gives selective, bright, and endured fluorescence signals in subcutaneous tumors and orthotopic tumors in mice models. These results indicate the potential of ROXSia as a lysosome-targeted optical agent for fluorescence-guided tumor resection.

RETRACTED: Radiosynthesis and biological evaluation of fluorine-18 labeled N-acetylgalactosamine derivative [18F]FPGalNAc for PET imaging of asialoglycoprotein receptor-positive tumors

The asialoglycoprotein receptor(ASGPR) is abundantly expressed on the surface of hepatocytes where it recognizes and endocytoses glycoproteins with galactosyl and N-acetylgalactosamine groups. ASGPR not only express on the surface of hepatocytes, but also express in several tumor cells (HepG2, A549 and HCT116). The purpose of this study was to develop a ASGPR-specific radiofluorinated ligand for positron emission tomography (PET) imaging in several tumor models. The radiosynthesis of [18F]FPGalNAc was initiated with fluorine-18 and 5-(p-toluenesulfonyl)-1-yne. The obtained 5-[18F]fluoro-1-pentyne intermediate was then reacted with 2-acetamido-2-deoxy-β-d-galactopyranosyl azide using "click chemistry" to produce the final product. The Kd of the product was determined in HepG2 cells at a range of concentrations of [18F]FPGalNAc. Cellular uptake and blocking experiments were also performed. In vivo biodistribution studies were performed in nude mice bearing HCT116 tumor and micro positron emission tomography/computed tomography (PET/CT) evaluations were then performed in tumor-bearing mice (HepG2, HCT116) models. The radiosynthesis of [18F]FPGalNAc required 50min with 5-6% RCY (radiochemical yield). The Kd of [18F]FPGalNAc to ASGPR in HepG2 cells was 0.25±0.02mM. Uptake values of 0.29% were observed within 30min of incubation with HepG2 cells, which could be blocked by 200mM d(+)-galactose (< 0.13%). The data of biodistribution revealed that the uptake of [18F]FPGalNAc was higher in kidneys and liver, and lower in muscle, bone and brain. In vivo micro PET studies, both HCT116 and HepG2 tumors showed high uptake for [18F]FPGalNAc, the radio of tumor/muscle (T/M) was 3.7 and 3.91, respectively. In vitro assays and in vivo PET/CT imaging and biodistribution studies showed that [18F]FPGalNAc represents a promising tumor imaging agent that can provide insight into ASGPR related disease.

A novel 99m Tc-diester complex as tumor targeting agent: Synthesis, radiolabeling, and biological distribution study.

The target of this study is the synthesis of a new diester derivative and radiolabeling with one of the most effective diagnostic radioisotopes to be investigated as a novel targeting radiotracer for tumor imaging. 10-[2-(9-Carboxynonanoyloxy)propoxy]-10-oxodecanoic acid was synthesized in excellent yield and characterized by Fourier-transform infrared spectroscopy, mass, 1 H-NMR, and 13 C-NMR spectra. The diester was technetium-99m (99m Tc) radiolabeled by direct technique using sodium dithionite as a reducing agent. The labeling parameters such as diester amount, reducing agent amount, pH of the medium, and reaction time were optimized. High radiochemical yield of 95.10 ± 0.41% and in vitro stability in serum up to 12 h have been obtained on complexation of the synthesized diester with Tc-99m. Evaluation of the diester anticancer activity against breast cancer cell line (MCF-7) showed high percent of inhibition about 61.5% at 100 μg/ml. The rhenium complex of the diester was synthesized and characterized by liquid chromatography-mass spectrometry (ESI) and elemental analysis depending on the strong chemical resemblance between Tc and Re. Biodistribution studies of 99m Tc-diester complex showed high target to nontarget ratio (T/NT) equals 6.24 ± 0.09 in tumor-bearing mice at 30-min postinjection, suggesting this complex could be used as hopeful solid tumor-imaging agent.

Production of 64Cu-labeled monobody for imaging of human EphA2-expressing tumors

We previously reported on the monobody E1, which specifically targets the tumor marker hEphA2. In this study, we labeled NOTA-conjugated E1 with 64Cu (64Cu-NOTA-E1) and evaluated biologic characteristics. The uptake of 64Cu-NOTA-E1 in PC3 cells (a human prostate cancer cell line) with high expression of hEphA2 increased in a time-dependent manner. In PC3 xenograft mice, 64Cu-NOTA-E1 injected via the tail vein allowed visualization of tumors on positron emission tomography after 1 h and the highest uptake measured at 24 h post-injection. By contrast, the radioactivity of other tissues either did not increase or decreased over 24 h. This indicates that 64Cu-NOTA-E1 has high tumor uptake and retention, with rapid clearance, and low background values in other tissues. Therefore, 64Cu-NOTA-E1 should be suitable as a novel PET imaging agent for hEphA2-expressing tumors.

Synthesis of 99mTc-p-SCN-Bzl-TCMC-bevacizumab for vascular endothelial growth factor (VEGF) receptor imaging using ovarian cancer model

In this study bevacizumab was labeled with 99mTc using p-SCN-Bzl-TCMC as a chelator for non invasive imaging of VEGF receptor in ovarian tumor Sprague Dawley rat and New Zealand rabbit models. High radiochemical purity and stability were observed using 0.4 mL of conjugated TCMC-bevacizumab. In vitro binding studies showed higher uptake of labeled conjugated bevacizumab with high metastatic SKOV-3 ipl cells as compared to poor metastatic SKOV-3. Biodistribution in rat model confirmed higher accumulation of labeled conjugated bevacizumab in the site infected with SKOV-3 ipl cells as compared to SKOV-3. Images of ovarian tumor rabbit model validated its specificity and efficacy as a promising ovarian tumor imaging agent.

SAT-313 Synaptojanin 2 Binding Protein Is Required for Efficient Somatostatin Receptor 2A Phosphorylation by G Protein Coupled Receptor Kinases and Signaling to the ERK/MAPK Pathway

Somatostatin receptor 2A (Sst2A) agonists are the primary pharmacological treatment for growth hormone (GH) secreting pituitary tumors to inhibit GH secretion and limit the destructive effects of these tumors. Sst2A agonists are also widely used as imaging agents for neuroendocrine tumors, and are under investigation for treatment of these cancers. However, despite the clinical importance of Sst2A agonists, regulatory mechanisms controlling Sst2A internalization and signaling are not fully understood. Sst2A contains a C-terminal PDZ binding site that serves as a docking platform for PDZ domain containing proteins. In an unbiased screen for PDZ domain proteins that can interact with Sst2A, we identified Synaptojanin 2 binding protein (SYNJ2BP) / Outer mitochondrial protein 25 (OMP25). SYNJ2BP is an outer mitochondrial protein that has been shown previously to promote the internalization of the Activin Type II receptor. We find that SYNJ2BP interacts with Sst2A in a ligand-dependent manner. Importantly, we show that SYNJ2BP promotes interaction of Sst2A with the G protein couple receptor kinase 2 (GRK2), and that siRNA-mediated knockdown of SYNJ2BP dramatically inhibits Sst2A phosphorylation by endogenous GRKs. Moreover, overexpression of SYNJ2BP strongly potentiates Sst2A phosphorylation on the GRK phosphorylation sites. Modulation of SYNJ2BP expression also regulates somatostatin-stimulated β-arrestin recruitment to the plasma membrane. Interestingly, in contrast to the large effects on Sst2A phosphorylation and β-arrestin recruitment, modulation of SYNJ2BP expression only caused a small change in ligand-stimulated receptor internalization. When we assessed downstream signaling, we found that SYNJ2BP overexpression potently stimulated receptor-dependent activation of ERK1/2, but had little effect on the ability of Sst2A to repress forskolin-stimulated cAMP production. Taken together, these data demonstrate for the first time that interaction of Sst2A with a PDZ domain protein affects receptor regulation and signaling. Because multiple PDZ domain containing proteins have been shown to interact with Sst2A, these data also suggest that interaction of Sst2A with this class of proteins may be an important regulatory mechanism to bias its function within the cell.

99m Tc-(EDDA/tricine)-HYNIC-GnRH analogue as a potential imaging probe for diagnosis of prostate cancer.

Prostate cancer is a serious threat to men's health, so it is necessary to develop the techniques for early detection of this malignancy. Radiolabeled peptides are the useful tools for diagnosis of prostate cancer. In this research, we designed a new HYNIC-conjugated GnRH analogue and labeled it by 99m Tc with tricine/EDDA as coligands. We used aminohexanoic acid (Ahx) as a hydrocarbon linker to generate 99m Tc-(tricine/EDDA)-HYNIC-Ahx-[DLys6 ]GnRH. The radiopeptide exhibited high radiochemical purity and stability in solution and serum. Two human prostate cancer cell lines LN-CaP and DU-145 were used for cellular experiments. The binding specificity and affinity of radiopeptide for LN-CaP were superior to DU-145 cells. The Kd values for LN-CaP and DU-145 cells were 41.91±7.03nM and 55.96±10.56nM, respectively. High kidney uptake proved that the main excretion route of radiopeptide was through the urinary system. The tumor/muscle ratio of 99m Tc-HYNIC-Ahx-[DLys6 ]GnRH was 4.14 at 1hr p.i. that decreased to 2.41 at 4hr p.i. in LN-CaP tumor-xenografted nude mice. The blocking experiment revealed that the tumor uptake was receptor-mediated. The lesion was visualized clearly using 99m Tc-[DLys6 ]GnRH at 1hr p.i. Accordingly, this research highlights the capability of 99m Tc-(tricine/EDDA)-HYNIC-Ahx-[DLys6 ]GnRH peptide as a promising agent for GnRHR-expressing tumor imaging.

Radiosynthesis and preclinical evaluation of [18F]FEM as a potential novel PET probe for tumor imaging

In the 21st century, the incidence and mortality of cancer, one of the most challenging diseases in the world, have rapidly increased. The purpose of this study was to develop 2-(2-[18F]fluoroethoxy)ethyl 4-methylbenzenesulfonate ([18F]FEM) as a positron emission tomography (PET) agent for tumor imaging. In this study, [18F]FEM was synthesized with a good radiochemical yield (45.4 ± 5.8%), high specific radioactivity (over 25 GBq/μmol), and commendable radiochemical purity (over 99%). The octanol/water partition coefficient of [18F]FEM was 1.44 ± 0.04. The probe demonstrated good stability in vitro (phosphate-buffered saline (PBS) and mouse serum (MS)), and binding specificity to five different tumor cell lines (A549, PC-3, HCC827, U87, and MDA-MB-231). PET imaging of tumor-bearing mice showed that [18F]FEM specifically accumulated at the tumor site of the five different tumor cell lines. The average tumor-to-muscle (T/M) ratio was over 2, and the maximum T/M values reached about 3.5. The biodistribution and dynamic PET imaging showed that most probes were metabolized by the liver, whereas a small part was metabolized by the kidney. Moreover, dynamic brain images and quantitative data showed [18F]FEM can quickly cross the blood brain barrier (BBB) and quickly fade out, thereby suggesting it may be a promising candidate probe for the imaging of brain tumors. The presented results demonstrated that [18F]FEM is a promising probe for tumor PET imaging.

Synthesis and evaluation of Al18F-NODA complex conjugated 2-(4-aminophenyl)benzothiazole as a potential tumor imaging agent

The objective of the study was to prepare and evaluate a 18F-radiolabled tracer (Al18F-5), derivated from the antitumor agent 2-(4-aminophenyl)benzothiazole, as a PET probe for tumor imaging. Al18F-5 was successfully prepared with approx. 40% radiochemical yield in aqueous phase. In in vitro cell uptake experiments and competition assay, Al18F-5 displayed good tumor-binding ability and specificity in HeLa cells (24.7 ± 0.9% ID/106 cells, IC50 = 63.8 ± 13.6 nM) and MCF-7 cells (6.8 ± 0.3% ID/106 cells, IC50 = 331.1 ± 33.7 nM). The nonradioactive compound, Al19F-5, visibly marked HeLa cells and MCF-7 cells but did not stain HEB cells in florescent staining, which further indicated the tumor-binding ability of Al18F-5. In in vivo PET imaging, HeLa and MCF-7 tumors were clearly delineated by specific accumulation of Al18F-5 in model mice. In biodistribution study, Al18F-5 exhibited good tumor uptake (4.66 ± 0.13% ID/g and 3.69 ± 0.56% ID/g, respectively), moderate tumor-to-muscle ratio (3.38 and 2.48, respectively) at 1 h post injection, which were in a good consistency with the results of PET imaging. In conclusion, Al18F-5 might be developed as a candidate PET probe for tumor imaging, though additional optimizations are still needed to improve pharmacokinetics in vivo.

Evaluation of Radiation dosimetry of 99mTc-HYNIC-PSMA and imaging in prostate cancer

This study aims to evaluate the radiation dosimetry of a new technetium-99m‒labelled small-molecule inhibitor of prostate-specific membrane antigen (HYNIC-Glu-Urea-A, 99mTc-HYNIC-PSMA) and its feasibility as a tumor-imaging agent in prostate cancer (PCa) patients. A total of 15 PCa patients were enrolled in this study. For the dosimetry study, 5 PCa patients received whole-body planar scans at 0.5 h, 1 h, 2 h, 4 h and 8 h after 99mTc-HYNIC-PSMA injection. The Dosimetry Toolkit (GE, Milwaukee) was used to process the data and segment the organs in the SPECT/CT images, which were then projected onto planar images. The organ-specific absorbed doses, total-body absorbed doses and 99mTc-HYNIC-PSMA effective doses of patients were calculated using OLINDA/EXM 1.1 software. Whole-body SPECT/CT images were also acquired from additional 10 prostate patients to investigate the feasibility of 99mTc-HYNIC-PSMA for imaging tumors by calculating the ratio of tumor-to-background tracer uptake at 2 h after 740 MBq administration. The total-body absorbed dose was 1.54E-03 ± 2.43E-04 mGy/MBq, and the effective dose was 3.72E-03 ± 4.5E-04 mSv/MBq. Compared to published studies of other similar PSMA tracers and 99mTc-targeted conventional tracers, the absorbed doses of 99mTc-HYNIC-PSMA in all organs showed that it could be used safely in the human body. In addition, 99mTc-HYNIC-PSMA showed high tracer uptake (with a tumor-to-background ratio of 9.42 ± 2.62) in the malignant lesions of PCa patients, making it a promising radiopharmaceutical imaging method for site-specific management of PCa.

Enhancing Tumor Targeting Efficiency of Radiolabeled Uridine (via) Incorporation into Nanocubosomal Dispersions.

Background: Several nanosystems are currently being utilized to enhance the targeting efficiency of several cancer chemotherapeutic agents. This study was designed to improve tumor accumulation of iodine-125 (125I)-uridine via incorporation into a nanocubosomal preparation. Materials and Methods: Nanocubosomes were prepared with the aid of Glycerol mono-oleate and Pluronic F127. Each prepared nanocubosomal preparation was adequately characterized by testing their particle size, polydispersity index (PDI), ζ potential (ZP), and transmission electron microscopy. The radiolabeling of uridine with 125I was attempted using several oxidizing agents to achieve a high radiochemical yield, and the factors affecting the reaction yield were studied in detail. A comparative biodistribution study of free 125I-uridine and 125I-uridine loaded nanocubosomes was performed in normal and tumor bearing mice. The biodistribution was evaluated by intravenous injection of the sterile test solution, and animals were anesthetized and dissected at different time intervals postinjection (p.i.). Results: 125I-uridine was obtained in a high radiochemical yield (92.5% ± 0.8%). Afterward, 125I uridine was incorporated in a selected nanocubosome formulation, which showed nanosized cubic particles (178.6 ± 0.90 nm) with PDI (0.301 ± 0.04) and a ZP (34.35 ± 0.4). The biodistribution studies revealed that 125I-uridine nanocubosomes showed higher tumor localization (3.1 ± 0.4%IA/g at 2 h p.i. and a tumor/muscle ratio of 6.2) compared with the free 125I-uridine (2.7% ± 0.4%IA/g at 2 h p.i. and a tumor/muscle ratio of 3.3). Conclusion: The results of this study confirmed that 125I-uridine loaded nanocubosome had better efficiency in targeting the tumor site, which makes it an adequate targeting agent for tumor imaging.

Genetic Encoding of Targeted Magnetic Resonance Imaging Contrast Agents for Tumor Imaging.

Tumor-selective contrast agents have the potential to aid in the diagnosis and treatment of cancer using noninvasive imaging modalities such as magnetic resonance imaging (MRI). Such contrast agents can consist of magnetic nanoparticles incorporating functionalities that respond to cues specific to tumor environments. Genetically engineering magnetotactic bacteria to display peptides has been investigated as a means to produce contrast agents that combine the robust image contrast effects of magnetosomes with the transgenic-targeting peptides displayed on their surface. This work reports the first use of magnetic nanoparticles that display genetically encoded pH low insertion peptide (pHLIP), a long peptide intended to enhance MRI contrast by targeting the extracellular acidity associated with the tumors. To demonstrate the modularity of this versatile platform to incorporate diverse targeting ligands by genetic engineering, we also incorporated the cyclic αv integrin-binding peptide iRGD into separate magnetosomes. Specifically, we investigate their potential for enhanced binding and tumor imaging both in vitro and in vivo. Our experiments indicate that these tailored magnetosomes retain their magnetic properties, making them well suited as T2 contrast agents, while exhibiting an increased binding compared to the binding in wild-type magnetosomes.

Preparation and evaluation of 99mTc-labeled HYNIC-palbociclib analogs for cyclin-dependent kinase 4/6-positive tumor imaging

Overexpression and amplification of cyclin-dependent kinase 4/6 (CDK4/6) occur in many cancers and may be the cause of resistance to CDK4/6 inhibitors in preclinical models. However, there are few investigations on the assessment of CDK4/6 expression in tumors or other tissues. Palbociclib, which was approved in 2015 to treat ER+/HER2-breast cancer in combination with letrozole, is a selective CDK4/6 inhibitor. In this study, an intermediate (compound 3), which could be hydrolyzed into the ligand (compound L) consisting of palbociclib as the bioactive molecule and 6-hydrazino nicotinamide (HYNIC) as the bifunctional chelator, was synthesized. Compound L was radiolabeled with 99mTc using tricine/TPPTS or tricine/TPPMS as co-ligands. 99mTc-tricine-TPPTS-L and 99mTc-tricine-TPPMS-L were prepared with high radiochemical purity without postlabeling purification. They had great in vitro stability. Both radiotracers were hydrophilic, but 99mTc-tricine-TPPTS-L had a lower log P value. In vitro cell uptake studies in MCF-7 cells showed that cellular uptake was blocked by preincubation with palbociclib, suggesting a CDK4/6-mediated uptake mechanism. Biodistribution in mice bearing MCF-7 tumors showed that 99mTc-tricine-TPPTS-L had higher tumor uptake than 99mTc-tricine-TPPMS-L, while they had comparable tumor-to-muscle and tumor-to-blood ratios. Radioactivity accumulation in tumors was obvious in micro-SPECT/CT images with 99mTc-tricine-TPPTS-L. When mice were preinjected with palbociclib, tumor uptake of 99mTc-tricine-TPPTS-L significantly decreased and the tumor accumulation was clearly lost, confirming CDK4/6 specificity. All results in this work indicated that 99mTc-tricine-TPPTS-L is a promising tumor imaging agent that targets CDK4/6.

Tumor Cell Membrane-Based Peptide Delivery System Targeting to Tumor Microenvironment for Cancer Immunotherapy and Diagnosis

\The development of effective delivery system for peptides targeting to the tumor microenvironment has always been a hot topic in the field of cancer diagnosis and therapy. A multifunctional delivery system by encapsulating superparamagnetic iron oxide nanoparticles (SPIO NPs) with tumor cell membrane obtained by hypotonic lysis followed by mechanical fragmentation was constructed to effectively deliver therapeutic peptides. SPIO nanoparticles were encapsulated with H460 lung cancer cell membranes (SPIO NP@M) and peptides consisted of PD-L1 inhibitory peptide (TPP-1) and MMP2 substrate peptide (PLGLLG) was conjugated to H460 membrane (SPIO NP@M-P). The abilities of homologous targeting, cytotoxicity, pharmacokinetics, and tumor targeting ability of SPIO NP@M-P were evaluated. TPP-1 peptide was delivered and released to the tumor microenvironment through the homotypic effect of tumor cell membrane and specific digestion by the tumor specific enzyme, MMP2. The newly developed delivery system (SPIO NP@M-P) for PD-L1 inhibitory peptide could effectively extend the half-life of the peptides (60 times longer) and meanwhile maintain the ability to re-activate T cell and inhibit the tumor growth in vitro and in vivo. Furthermore, SPIO NPs in the system could be used as a tumor imaging agent and thus indicate the effect of peptide treatment. The SPIO NP@M might provide a promising theranostic platform for therapeutic peptide application in cancer therapy.

Synthesis and preliminary evaluation of a 99mTc labelled deoxyglucose complex {[99mTc]DTPA-bis(DG)} as a potential SPECT based probe for tumor imaging

[99mTc]DTPA-bis(DG): a potent tumor imaging probe.

THE ROLE OF TUMOR-SEEKING RADIOPHARMACEUTICALS IN THE DIAGNOSIS AND MANAGEMENT OF ADRENAL TUMORS.

The variety of tumor-seeking radiopharmaceuticals, which are currently in clinical use, may have a potential role as imaging agents for adrenal gland tumors, due to physiological characteristics of this organ. The purpose of this study was to evaluate the diagnostic potential of 99mTc-HYNIC-TOC, 99mTc(V)-DMSA, and 99mTc-MIBI in the assessment of adrenal tumors, by correlating with imaging findings and histopathologic results. The research is designed as a cross-sectional prospective study. The study included 50 patients with adrenal tumors (19 hormone-secreting and 31 nonfunctioning) and 23 controls without adrenal involvement. In all patients, single-photon emission computed tomography (SPECT) was performed, using qualitative and semiquantitative analysis. The tumor to non-tumor tracer uptake was conducted by using a region-of-interest technique. Adrenal to background (A/B) ratio was calculated in all cases. 99mTc-HYNIC-TOC scintigraphy showed a high statistical significance between A/B ratios, while other two tracers resulted in a lower sensitivity, specificity and accuracy. Futhermore, 99mTc-HYNIC-TOC could have a high diagnostic yield to detect adrenal tumors (the receiver-operating-characteristic curve analysis, A/B ratio cut-off value of 8.40). A semiquantitative SPECT analysis showed that 99mTc-HYNIC-TOC is a highly sensitive tumor-seeking agent for the accurate localization of adrenal tumors.

Hypocrellin Derivative-Loaded Calcium Phosphate Nanorods as NIR Light-Triggered Phototheranostic Agents with Enhanced Tumor Accumulation for Cancer Therapy.

Dopamine modified hypocrellin B (DAHB) derivative-loaded calcium phosphate nanorods (DAHB@CaP NRs) were prepared as a novel phototheranostic agent for effective tumor imaging and therapy. DAHB@CaP NRs were obtained through microwave treatment using DAHB, CaCl2 , NH3 ⋅H2 O, and H3 PO4 as precursors. The DAHB@CaP NRs possessed the following advantages: 1) efficient absorption in the near-infrared (NIR) region from 650 nm to 800 nm; 2) maximum NIR emission at approximately 735 nm; 3) enhanced cellular uptake efficiency in vitro and in vivo; and 4) efficient inhibition of tumor growth and low biotoxicity. These properties indicate the high capability of DAHB@CaP NRs for NIR fluorescence (FL) imaging-guided photodynamic therapy of cancer, thus offering promising new prospects for clinical applications.

Tumor Contrast Imaging with Gas Vesicles by Circumventing the Reticuloendothelial System

Gas vesicles (GVs) are nanosized structures (45–800 nm) and have been reported to produce non-linear contrast signals, making them an attractive agent for molecular targeting of tumors. One barrier to their use for pre-clinical oncology studies is rapid uptake into the reticuloendothelial system (RES) and consequent rapid decrease in contrast signal after infusion ends and low signal on reperfusion after a bubble burst sequence. The purpose of this study was to examine suppression of the RES and surface modification of GVs to prolong contrast circulation in tumors for ultrasound imaging. Ultrasound imaging to measure dynamics of contrast signal intensity in tumor models was carried out using a 21-MHz high-frequency array transducer with the Vevo 2100 ultrasound system. The non-linear contrast signal from intravenously injected GVs compared with peak enhancement was measured during contrast wash-out and on reperfusion after a contrast burst sequence. Disrupting the RES by saturating the macrophage population or chemically inhibiting the Kupffer cell population with gadolinium or Intralipid preserves 62%–88% of GVs’ contrast enhancement relative to peak during the wash-out phase and 32%–56% on reperfusion compared with 38% and 14%, respectively, for no disruption of the RES, indicating longer circulation of GVs in the tumor. Additionally, coating the GVs with 2-, 5- or 10-kDa polyethylene glycol (PEG) chains resulted in >70% contrast signal retention in the tumors during wash-out and, for 5- or 10-kDa PEG chains, a return to >45% of peak contrast signal on reperfusion. These findings indicate that GVs can be used as a contrast agent for tumor imaging and that disruption of the RES improved recirculation and maintained contrast enhancement caused by GVs in the tumors.

Synthesis and biological evaluation of [18F](2S,4S)4-(3-fluoropropyl) arginine as a tumor imaging agent

Designing novel 18F-labeled amino acid derivatives for targeted amino acid transporters is an attractive strategy for the development of therapeutic and diagnostic agents for cancer therapy. In this work, we have developed a novel 3-fluoropropyl analog of arginine, namely, (2S,4S)4-[18F]FPArg, [18F]1, to be used as a probe for studying arginine metabolism. Optically pure and labeled with 18F and 19F, (2S,4S)4-(3-fluoropropyl)arginine was synthesized and isolated in high radiochemical purity (>95%). Invitro uptake assays in human MCF-7 cells revealed that [18F]1 enters cells mainly via sodium-independent cationic amino acid transporters and was inhibited >62% by arginine. [18F]1 showed a high cellular uptake of 7.3 ± 0.24% and 6.07 ± 0.3% uptake/100 mg protein after incubation in MCF-7 and MDA-MB-231 cells for 120 min, respectively. Invivo biodistribution studies demonstrated that [18F]1 provided high tumor uptake and high tumor to muscle ratios (5:1 at the 30 and 60 min time points). Invivo PET imaging studies demonstrated tumor-specific uptake in nude mice bearing MCF-7 breast tumors with an excellent tumor-to-muscle ratio. These results suggest that [18F]1 is a promising tracer for clinical breast cancer imaging and may be used to diagnose and monitor diseases that are associated with arginine metabolism.