Evaluation of [18F]fluoroestradiol and ChRERα as a gene expression PET reporter system in rhesus monkey brain.

Positron emission tomography (PET) reporter systems are a valuable means of estimating the level of expression of a transgene in vivo. For example, the safety and efficacy of gene therapy approaches for the treatment of neurological and neuropsychiatric disorders could be enhanced via the monitoring of exogenous gene expression levels in the brain. The present study evaluated the ability of a newly developed PET reporter system, [18F]fluoroestradiol and the estrogen receptor-based PET reporter ChRERα, to monitor expression levels of a shRNA designed to suppress choline acetyltransferase (ChAT) expression in rhesus monkey brain. The ChRERα gene and shRNA were expressed from the same transcript via lentivirus injected into monkey striatum. In two monkeys that received injections of viral vector, [18F]fluoroestradiol binding increased by 70% and 86%, respectively, at the target sites compared to pre-injection, demonstrating that ChRERα expression could be visualized in vivo with PET imaging. Postmortem immunohistochemistry confirmed that ChAT expression was significantly suppressed in regions in which [18F]fluoroestradiol uptake was increased. The consistency between PET imaging and immunohistochemical results suggests that [18F]fluoroestradiol and ChRERα can serve as a PET reporter system in rhesus monkey brain for in vivo evaluation of the expression of potential therapeutic agents, such as shRNAs.

In vivo evaluation of a novel 18F-labeled PET radioligand for translocator protein 18 kDa (TSPO) in monkey brain.

PURPOSE: [18F]SF51 was previously found to have high binding affinity and selectivity for 18 kDa translocator protein (TSPO) in mouse brain. This study sought to assess the ability of [18F]SF51 to quantify TSPO in rhesus monkey brain. METHODS: Positron emission tomography (PET) imaging was performed in monkey brain (n = 3) at baseline and after pre-blockade with the TSPO ligands PK11195 and PBR28. TSPO binding was calculated as total distribution volume corrected for free parent fraction in plasma (VT/fP) using a two-tissue compartment model. Receptor occupancy and nondisplaceable uptake were determined via Lassen plot. Binding potential (BPND) was calculated as the ratio of specific binding to nondisplaceable uptake. Time stability of VT was used as an indirect probe to detect radiometabolite accumulation in the brain. In vivo and ex vivo experiments were performed in mice to determine the distribution of the radioligand. RESULTS: After [18F]SF51 injection, the concentration of brain radioactivity peaked at 2.0 standardized uptake value (SUV) at ~ 10 min and declined to 30% of the peak at 180 min. VT/fP at baseline was generally high (203 ± 15 mL· cm-3) and decreased by ~ 90% after blockade with PK11195. BPND of the whole brain was 7.6 ± 4.3. VT values reached levels similar to terminal 180-min values by 100 min and remained relatively stable thereafter with excellent identifiability (standard errors < 5%), suggesting that no significant radiometabolites accumulated in the brain. Ex vivo experiments in mouse brain showed that 96% of radioactivity was parent. No significant uptake was observed in the skull, suggesting a lack of defluorination in vivo. CONCLUSION: The results demonstrate that [18F]SF51 is an excellent radioligand that can quantify TSPO with a good ratio of specific to nondisplaceable uptake and has minimal radiometabolite accumulation in brain. Collectively, the results suggest that [18F]SF51 warrants further evaluation in humans.

High-performance multifunctional porous iron Acetylacetonate/N, O-doped carbon nanospheres for electromagnetic wave absorption at 2-18 GHz and methyl orange absorption.

Nowadays, multifunction is regarded as an advanced development direction of new-generation electromagnetic wave absorption (EMWA) materials to fulfill the ever-growing demands in complex environment and situation. Environmental pollution and electromagnetic pollution are all difficult problems for human beings all the time. Now, there is no multifunctional materials for collaborative treatment of environmental and electromagnetic pollution. Herein, We synthesized nanospheres with divinyl benzene (DVB) and N-[3-(dimethylamino)propyl]methacrylamide (DMAPMA), using a simple one-pot method. After calcination at 800 ℃ in N2, porous N, O-doped porous carbon materials were prepared. By regulating the mole ratio of DVB and DMAPMA, the ratio was 5:1 reached excellent EMWA property. Remarkably, the introduction of iron acetylacetonate into the reaction of DVB and DMAPMA was effective in enhancing the absorption bandwidth to 8.00 GHz at a 3.74 mm thickness, which depended on the synergistic effects from dielectric and magnetic losses. Simultaneously, the Fe-doped carbon materials had a methyl orange adsorption capacity. The adsorption isotherm conformed to the Freundlich model. After methyl orange absorption, the EMWA property did not greatly change. Thus, this research paves the way for the creation of multifunctional materials to solve environmental pollution and electromagnetic pollution together.

Discovery of a High-Affinity Fluoromethyl Analog of [11C]5-Cyano-N-(4-(4-methylpiperazin-1-yl)-2-(piperidin-1-yl)phenyl)furan-2-carboxamide ([11C]CPPC) and Their Comparison in Mouse and Monkey as Colony-Stimulating Factor 1 Receptor Positron Emission Tomography Radioligands.

[11C]CPPC has been advocated as a radioligand for colony-stimulating factor 1 receptor (CSF1R) with the potential for imaging neuroinflammation in human subjects with positron emission tomography (PET). This study sought to prepare fluoro analogs of CPPC with higher affinity to provide the potential for labeling with longer-lived fluorine-18 (t 1/2 = 109.8 min) and for delivery of higher CSF1R-specific PET signal in vivo. Seven fluorine-containing analogs of CPPC were prepared and four were found to have high inhibitory potency (IC50 in low to sub-nM range) and selectivity at CSF1R comparable with CPPC itself. One of these, a 4-fluoromethyl analog (Psa374), was investigated more deeply by labeling with carbon-11 (t 1/2 = 20.4 min) for PET studies in mouse and monkey. [11C]Psa374 showed high peak uptake in monkey brain but not in mouse brain. Pharmacological challenges revealed no CSF1R-specific binding in either species at baseline. [11C]CPPC also failed to show specific binding at baseline. Moreover, both [11C]Psa374 and [11C]CPPC showed brain efflux transporter substrate behavior in both species in vivo, although Psa374 did not show liability toward human efflux transporters in vitro. Further development of [11C]Psa374 in non-human primate models of neuroinflammation with demonstration of CSF1R-specific binding would be required to warrant the fluorine-18 labeling of Psa374 with a view to possible application in human subjects.

Comprehensive analysis of transcriptome and metabolome analysis reveal new targets of Glaesserella parasuis glucose-specific enzyme IIBC (PtsG).

The ptsG (hpIIBCGlc) gene, belonging to the glucose-specific phosphotransferase system, encodes the bacterial glucose-specific enzyme IIBC. In this study, the effects of a deletion of the ptsG gene were investigated by metabolome and transcriptome analyses. At the transcriptional level, we identified 970 differentially expressed genes between ΔptsG and sc1401 (Padj<0.05) and 2072 co-expressed genes. Among these genes, those involved in methane metabolism, amino sugar and nucleotide sugar metabolism, starch and sucrose metabolism, pyruvate metabolism, phosphotransferase system (PTS), biotin metabolism, Two-component system and Terpenoid backbone biosynthesis showed significant changes in the ΔptsG mutant strain. Metabolome analysis revealed that a total of 310 metabolites were identified, including 20 different metabolites (p < 0.05). Among them, 15 metabolites were upregulated and 5 were downregulated in ΔptsG mutant strain. Statistical analysis revealed there were 115 individual metabolites having correlation, of which 89 were positive and 26 negative. These metabolites include amino acids, phosphates, amines, esters, nucleotides, benzoic acid and adenosine, among which amino acids and phosphate metabolites dominate. However, not all of these changes were attributable to changes in mRNA levels and must also be caused by post-transcriptional regulatory processes. The knowledge gained from this lays the foundation for further study on the role of ptsG in the pathogenic process of Glaesserella parasuis (G.parasuis).

Instant diagnosis of gastroscopic biopsy via deep-learned single-shot femtosecond stimulated Raman histology.

Gastroscopic biopsy provides the only effective method for gastric cancer diagnosis, but the gold standard histopathology is time-consuming and incompatible with gastroscopy. Conventional stimulated Raman scattering (SRS) microscopy has shown promise in label-free diagnosis on human tissues, yet it requires the tuning of picosecond lasers to achieve chemical specificity at the cost of time and complexity. Here, we demonstrate that single-shot femtosecond SRS (femto-SRS) reaches the maximum speed and sensitivity with preserved chemical resolution by integrating with U-Net. Fresh gastroscopic biopsy is imaged in <60 s, revealing essential histoarchitectural hallmarks perfectly agreed with standard histopathology. Moreover, a diagnostic neural network (CNN) is constructed based on images from 279 patients that predicts gastric cancer with accuracy >96%. We further demonstrate semantic segmentation of intratumor heterogeneity and evaluation of resection margins of endoscopic submucosal dissection (ESD) tissues to simulate rapid and automated intraoperative diagnosis. Our method holds potential for synchronizing gastroscopy and histopathological diagnosis.

Impact of intracellular response regulator QseB in quorum sensing regulatory network in a clinical isolate SC1401 of Glaesserella parasuis.

Two component systems (TCS) mediate specific responses to different conditions and/or pressures. In the quorum sensing Glaesserella parasuis (QSE) BC TCS, qseB, as a response regulator, is closely related to the transcriptional regulation of multiple downstream genes. In this study, the effects of qseB gene deletion, which encodes the response regulator of population density sensing in G. parasuis, were studied through biological characteristics and metabolomic analysis. Based on previous research, we further explored the virulence of ΔqseB mutant strains through cell morphology, adhesion and invasion. The ΔqseB mutant and parent strains were sequenced by metabolome and combined with the previous transcriptome sequencing results for joint analysis. This study aims to clarify the regulatory effect of QseB on the virulence of G. parasuis and lay the foundation for revealing the pathogenic mechanism of G. parasuis. We detected 476 different metabolites, of which 30 metabolites (6.3%) had a significant difference in abundance between SC1401 and ΔqseB (p < 0.05). We conducted a comparative analysis of pathway enrichment on the transcriptome and metabolome, and found that the two omics participate in seven metabolic pathways together. The top 10 KEGG pathways with the largest number of genes and metabolites identified in this experiment are ABC transporters, Biosynthesis of secondary metabolites, Cysteine and methionine metabolism, Purine metabolism, Pyrimidine metabolism, Metabolic pathways, and Nicotinate and nicotinamide metabolism. Analysis of metabolome sequencing results showed that differential metabolites were also enriched in metabolic pathways, such as Purine metabolism, cGMP-PKG signaling pathway and cAMP signaling pathway, which were not found in transcriptome sequencing data. The internal coloration of the mutant strain ΔqseB was uneven, and the adhesion and invasion ability of PAM cell lines were significantly reduced. We speculate that QseB may affect the adhesion and invasion ability of Glaesserella parasuis by influencing substance transport and signal transduction.

First-in-Human Evaluation of 18F-PF-06445974, a PET Radioligand That Preferentially Labels Phosphodiesterase-4B.

Phosphodiesterase-4 (PDE4), which metabolizes the second messenger cyclic adenosine monophosphate (cAMP), has 4 isozymes: PDE4A, PDE4B, PDE4C, and PDE4D. PDE4B and PDE4D have the highest expression in the brain and may play a role in the pathophysiology and treatment of depression and dementia. This study evaluated the properties of the newly developed PDE4B-selective radioligand 18F-PF-06445974 in the brains of rodents, monkeys, and humans. Methods: Three monkeys and 5 healthy human volunteers underwent PET scans after intravenous injection of 18F-PF-06445974. Brain uptake was quantified as total distribution volume (V T) using the standard 2-tissue-compartment model and serial concentrations of parent radioligand in arterial plasma. Results: 18F-PF-06445974 readily distributed throughout monkey and human brain and had the highest binding in the thalamus. The value of V T was well identified by a 2-tissue-compartment model but increased by 10% during the terminal portions (40 and 60 min) of the monkey and human scans, respectively, consistent with radiometabolite accumulation in the brain. The average human V T values for the whole brain were 9.5 ± 2.4 mL ⋅ cm-3 Radiochromatographic analyses in knockout mice showed that 2 efflux transporters-permeability glycoprotein (P-gp) and breast cancer resistance protein (BCRP)-completely cleared the problematic radiometabolite but also partially cleared the parent radioligand from the brain. In vitro studies with the human transporters suggest that the parent radioligand was a partial substrate for BCRP and, to a lesser extent, for P-gp. Conclusion: 18F-PF-06445974 quantified PDE4B in the human brain with reasonable, but not complete, success. The gold standard compartmental method of analyzing brain and plasma data successfully identified the regional densities of PDE4B, which were widespread and highest in the thalamus, as expected. Because the radiometabolite-induced error was only about 10%, the radioligand is, in the opinion of the authors, suitable to extend to clinical studies.

The Advancement of Gas-Generating Nanoplatforms in Biomedical Fields: Current Frontiers and Future Perspectives.

Diverse gases (NO, CO, H2 S, H2 , etc.) have been widely applied in the medical intervention of various diseases, including cancer, cardiovascular disease, ischemia-reperfusion injury, bacterial infection, etc., attributing to their inherent biomedical activities. Although many gases have many biomedical activities, their clinical use is still limited due to the rapid and free diffusion behavior of these gases molecules, which may cause potential side effects and/or ineffective treatment. Gas-generating nanoplatforms (GGNs) are effective strategies to address the aforementioned challenges of gas therapy by preventing gas production or release at nonspecific sites, enhancing GGNs accumulation at targeted sites, and controlling gas release in response to exogenous (UV, NIR, US, etc.) or endogenous (H2 O2 , GSH, pH, etc.) stimuli at the lesion site, further maintaining gas concentration within the effective range and achieving the purpose of disease treatment. This review comprehensively summarizes the advancements of "state-of-the-art" GGNs in the recent three years, with emphasis on the composition, structure, preparation process, and gas release mechanism of the nanocarriers. Furthermore, the therapeutic effects and limitations of GGNs in preclinical studies using cell/animal models are discussed. Overall, this review enlightens the further development of this field and promotes the clinical transformation of gas therapy.

Simultaneous and Efficient Removal of Oleophilic and Hydrophilic Stains from Polyurethane by the Combination of Easy-Cleaning and Self-Cleaning.

The simultaneous and efficient removal of oleophilic and hydrophilic stains from polyurethane (PU) is realized by combining the easy-cleaning from the hydrophilic thermoresponsive hydrogel coating containing acrylamide (AAm), gum arabic (GA), and (ethylene glycol) methyl ether methacrylate (OEGMA300) P(GA/AAm/OEGMA300) and the self-cleaning from the embedded nonmetallic photocatalyst g-C3N4. Due to the existence of strong hydrogen bonds between the hydroxyl groups in the hybrid hydrogel coating and the hydroxyl/carboxyl groups in the plasma-treated PU, the hybrid hydrogel coating is very stable on PU. Simultaneously, the acrylamide network in the hybrid hydrogel coating enhances its mechanical strength. Because the transition temperature of OEGMA300 is well above the room temperature, the cross-linked coating remains hydrophilic in ambient conditions. Thus, oleophilic stains, such as oil and grease, can be easily removed from the coating surface. In addition, the embedded photocatalyst g-C3N4 in the hybrid hydrogel coating introduces the extra capability of decomposing organic compounds under sunshine, which favors the removal of hydrophilic stains such as dyes and wines. After sunlight illumination and simply rinsing with water, both hydrophilic and oleophilic stains can be easily removed. Moreover, this joint cleaning performance can work for a long time. Even after four consecutive cycles, both the easy-cleaning to oleophilic stains by the hydrophilic hydrogel surface and self-cleaning to the hydrophilic stains by the embedded g-C3N4 remain unchanged.

Kinetic control of Phytic acid/Lixisenatide/Fe (III) ternary nanoparticles assembly process for sustained peptide release.

The preferable choice of sustained peptide delivery systems is generally polymer-based microspheres in which their large particle size, wide size distribution, low drug encapsulation efficacy, poor colloidal stability, and undesirable burst release eventually hinder their clinical translation. In this study, a nanoscale ternary Lixisenatide (Lix) sustained delivery system based on strong multivalent interactions (electrostatic and coordination complexation) among small molecular phytic acid (PA), Lix and Fe3+ was developed. Flash nanocomplexation (FNC) was utilized to facilitate the rapid and efficient mixing of the three components and kinetically control the assembly process that enabled dynamic balance of two competitive chemical reactions with different kinetic rates (slow chemical reaction of PA/Lix and fast chemical reaction of PA/Fe3+) to generate structural uniform ternary nanoparticles and avoid heterogeneous complexes. By tuning the mixing conditions (i.e., flow rate, mass ratio, concentration, pH value, etc.), the ternary PA/Lix/Fe3+ nanoparticles were assembled with reproducible production in a manner of high uniformity and scalability, achieving small size (∼50 nm), uniform composition (PDI: ∼0.12), favourable colloidal stability, high encapsulation efficiency (∼100%), and tunable drug release kinetics. The optimized formulation exhibited a minor Lix release (<20%) in the first day and extended peptide release period over 8 days. Unexpectedly, upon a single injection administration, the as-prepared formulation (600 µg/kg) rapidly brought the high BGL (∼30 mmol/L) back to normal range (<10 mmol/L) within the initial 6 h and achieved a 180 h glycemic control in T2D mouse model. Moreover, this sustained peptide delivery system demonstrated a repeatable hypoglycemic effects and significantly suppressed the pathological damage of major organs following multiple injection. This sustained peptide delivery system with aqueous, facile and reproducible preparation process possesses good biocompatibility, tunable release kinetics, and prolonged hypoglycemic effects, portending its great translational potential in the chronic disease treatment.

Discovery of Highly Potent Adenosine A1 Receptor Agonists: Targeting Positron Emission Tomography Probes.

Adenosine receptor (AR) radiotracers for positron emission tomography (PET) have provided knowledge on the in vivo biodistribution of ARs in the central nervous system (CNS), which is of therapeutic interest for various neuropsychiatric disorders. Additionally, radioligands that can image changes in endogenous adenosine levels in different physiological and pathological conditions are still lacking. The binding of known antagonist adenosine A1 receptor (A1R) radiotracer, [11C]MDPX, failed to be inhibited by elevated endogenous adenosine in a rodent PET study. Since most of the known AR PET radiotracers were antagonists, we propose that an A1R agonist radioligand may possess higher sensitivity to measure changes in endogenous adenosine concentration. Herein, we report our latest findings toward the development of a full agonist adenosine A1 radioligand for PET. Based on a 3,5-dicyanopyridine template, 16 new derivatives were designed and synthesized to optimize both binding affinity and functional activity, resulting in two full agonists (compounds 27 and 29) with single-digit nanomolar affinities and good subtype selectivity (A1/A2A selectivity of ∼1000-fold for compound 27 and 29-fold for compound 29). Rapid O-[11C]methylation provided [11C]27 and [11C]29 in high radiochemical yields and radiochemical purity. However, subsequent brain PET imaging in rodents showed poor brain permeability for both radioligands. An in vivo PET study using knockout mice for MDR 1a/a, BCRP, and MRP1 indicated that these compounds might be substrates for brain efflux pumps. In addition, in silico evaluation using multiparameter optimization identified high molecular weight and high polar surface area as the main molecular descriptors responsible for low brain penetration. These results will provide further insight toward development of full agonist adenosine A1 radioligands and also highly potent CNS A1AR drugs.

Ultrasmall Gd@Cdots as a radiosensitizing agent for non-small cell lung cancer.

High-Z nanoparticles (HZNPs) afford high cross-section for high energy radiation and have attracted wide attention as a novel type of radiosensitizer. However, conventional HZNPs are often associated with issues such as heavy metal toxicity, suboptimal pharmacokinetics, and low cellular uptake. Herein, we explore gadolinium-intercalated carbon dots (Gd@Cdots) as a dose-modifying agent for radiotherapy. Gd@Cdots are synthesized through a hydrothermal reaction with an ultrasmall size (∼3 nm) and a high Gd content. Gd@Cdots can significantly increase hydroxyl radical production under X-ray irradiation; this is attributed to not only the photoelectric effects of Gd, but also the surface catalytic effects of carbon. Because carbon is biologically and chemically inert, Gd@Cdots show low Gd leakage and minimal toxicity. In vitro studies confirm that Gd@Cdots can efficiently enhance radiation-induced cellular damage, causing elevated double strand breaks, lipid peroxidation, and mitochondrial depolarization. When tested in mice bearing non-small cell lung cancer H1299 tumors, intravenously injected Gd@Cdots plus radiation leads to improved tumor suppression and animal survival relative to radiation alone while causing no detectable toxicity. Our studies suggest a great potential of Gd@Cdots as a safe and efficient radiosensitizer.

Improving Tumor-to-Background Contrast through Hydrophilic Tetrazines: The Construction of 18 F-Labeled PET Agents Targeting Nonsmall Cell Lung Carcinoma.

Bioorthogonal reactions have been widely used in the biomedical field. 18 F-TCO/Tetrazine ligation is the most reactive radiolabelled inverse electron demand Diels-Alder reaction, but its application had been limited due to modest contrast ratios of the resulting conjugates. Herein, we describe the use of hydrophilic tetrazines to improve tumor-to-background contrast of neurotensin receptor targeted PET agents. PET agents were constructed using a rapid Diels-Alder reaction of the radiolabeled trans-cyclooctene (18 F-sTCO) with neurotensin (NT) conjugates of a 3,6-diaryltetrazine, 3-methyl-6-aryltetrazine, and a derivative of 3,6-di(2-hydroxyethyl)tetrazine. Although cell binding assays demonstrated all agents have comparable binding affinity, the conjugate derived from 3,6-di(2-hydroxyethyl)tetrazine demonstrated the highest tumor to muscle contrast, followed by conjugates of the 3-methyl-6-aryltetrazine and 3,6-diaryltetrazine.

Synthesis and initial evaluation of radioactive 5-I-α-methyl-tryptophan: a Trp based agent targeting IDO-1.

A synthetic approach is established to achieve radioactive 5-I-α-methyl-tryptophan (5-I-AMT). An enzyme based assay demonstrated that 5-I-AMT is a substrate of IDO-1. The in vivo distribution and imaging potential of 5-I-AMT were explored with a B16F10 tumor model using I-124 as the radiotag.

Perfluorocarbon-based O2 nanocarrier for efficient photodynamic therapy.

Tumor hypoxia is considered as one of the major factors that limit the efficiency of photodynamic therapy (PDT), in which oxygen (O2) is needed to generate singlet oxygen (1O2) for cell destruction. Inspired by the excellent O2 carrying ability of perfluorocarbon molecules in artificial blood, we prepared a series of polymer micelles with a perfluorocarbon core to carry both photo-sensitizer and O2 to the tumor site, aiming to improve PDT efficiency. We found that the accelerated generation of 1O2 correlated with the increased perfluorocarbon amount in solution. In vitro cell study further showed that the new perfluorocarbon formulation not only improved the production of 1O2, leading to enhanced photodynamic therapy efficiency, but also significantly reduced cell toxicity when compared with the one without these perfluoro units. This work provides a new option for improving PDT efficiency with the new perfluorocarbon-incorporated nanoplatform.

Improved Tumor Uptake by Optimizing Liposome Based RES Blockade Strategy.

Minimizing the sequestration of nanomaterials (NMs) by the reticuloendothelial system (RES) can enhance the circulation time of NMs, and thus increase their tumor-specific accumulation. Liposomes are generally regarded as safe (GRAS) agents that can block the RES reversibly and temporarily. With the help of positron emission tomography (PET), we monitored the in vivo tissue distribution of 64Cu-labeled 40 × 10 nm gold nanorods (Au NRs) after pretreatment with liposomes. We systematically studied the effectiveness of liposome administration by comparing (1) differently charged liposomes; (2) different liposome doses; and (3) varying time intervals between liposome dose and NR dose. By pre-injecting 400 µmol/kg positively charged liposomes into mice 5 h before the Au NRs, the liver and spleen uptakes of Au NRs decreased by 30% and 53%, respectively. Significantly, U87MG tumor uptake of Au NRs increased from 11.5 ± 1.1 %ID/g to 16.1 ± 1.3 %ID/g at 27 h post-injection. Quantitative PET imaging is a valuable tool to understand the fate of NMs in vivo and cationic liposomal pretreatment is a viable approach to reduce RES clearance, prolong circulation, and improve tumor uptake.

Clinical Translation of a Dual Integrin αvß3- and Gastrin-Releasing Peptide Receptor-Targeting PET Radiotracer, 68Ga-BBN-RGD.

This study aimed to document the first-in-human application of a 68Ga-labeled heterodimeric peptide BBN-RGD (bombesin-RGD) that targets both integrin αvß3 and gastrin-releasing peptide receptor (GRPR). We evaluated the safety and assessed the clinical diagnostic value of 68Ga-BBN-RGD PET/CT in prostate cancer patients in comparison with 68Ga-BBN. METHODS: Five healthy volunteers (4 men and 1 woman; age range, 28-53 y) were enrolled to validate the safety of 68Ga-BBN-RGD. Dosimetry was calculated using the OLINDA/EXM software. Thirteen patients with prostate cancer (4 newly diagnosed and 9 posttherapy) were enrolled. All the patients underwent PET/CT scans 15-30 min after intravenous injection of 1.85 MBq (0.05 mCi) per kilogram of body weight of 68Ga-BBN-RGD and also accepted 68Ga-BBN PET/CT within 2 wk for comparison. RESULTS: With a mean injected dose of 107.3 ± 14.8 MBq per patient, no side effect was found during the whole procedure and 2 wk follow-up, demonstrating the safety of 68Ga-BBN-RGD. A patient would be exposed to a radiation dose of 2.90 mSv with an injected dose of 129.5 MBq (3.5 mCi), which is much lower than the dose limit set by the Food and Drug Administration. In 13 patients with prostate cancer diagnosed by biopsy, 68Ga-BBN-RGD PET/CT detected 3 of 4 primary tumors, 14 metastatic lymph nodes, and 20 bone lesions with an SUVmax of 4.46 ± 0.50, 6.26 ± 2.95, and 4.84 ± 1.57, respectively. Only 2 of 4 primary tumors, 5 lymph nodes, and 12 bone lesions were positive on 68Ga-BBN PET/CT, with the SUVmax of 2.98 ± 1.24, 4.17 ± 1.89, and 3.61 ± 1.85, respectively. CONCLUSION: This study indicates the safety and efficiency of a new type of dual integrin αvß3- and GRPR-targeting PET radiotracer in prostate cancer diagnosis and staging.

DCE-MRI-Derived Parameters in Evaluating Abraxane-Induced Early Vascular Response and the Effectiveness of Its Synergistic Interaction with Cisplatin.

Our previous studies revealed molecular alterations of tumor vessels, varying from immature to mature alterations, resulting from Abraxane, and demonstrated that the integrin-specific PET tracer 18F-FPPRGD2 can be used to noninvasively monitor such changes. However, changes in the tumor vasculature at functional levels such as perfusion and permeability are also important for monitoring Abraxane treatment outcomes in patients with cancer. The purpose of this study is to further investigate the vascular response during Abraxane therapy and the effectiveness of its synergistic interaction with cisplatin using Dynamic contrast enhanced-magnetic resonance imaging (DCE-MRI). Thirty MDA-MB-435 tumor mice were randomized into three groups: PBS control (C group), Abraxane only (A group), and sequential treatment with Abraxane followed by cisplatin (A-P group). Tumor volume was monitored based on caliper measurements. A DCE-MRI protocol was performed at baseline and day 3. The Ktrans, Kep and Ve were calculated and compared with CD31, α-SMA, and Ki67 histology data. Sequential treatment with Abraxane followed by cisplatin produced a significantly greater inhibition of tumor growth during the three weeks of the observation period. Decreases in Ktrans and Kep for the A and A-P groups were observed on day 3. Immunohistological staining suggested vascular remodeling during the Abraxane therapy. The changes in Ktrans and Kep values were correlated with alterations in the permeability of the tumor vasculature induced by the Abraxane treatment. In conclusion, Abraxane-mediated permeability variations in tumor vasculature can be quantitatively visualized by DCE-MRI, making this a useful method for studying the effects of early cancer treatment, especially the early vascular response. Vascular remodeling by Abraxane improves the efficiency of cisplatin delivery and thus results in a favorable treatment outcome.

Al[18F]NOTA-T140 Peptide for Noninvasive Visualization of CXCR4 Expression.

PURPOSE: Chemokine receptor CXCR4 plays an important role in tumor aggressiveness, invasiveness, and metastasis formation. Quantification of CXCR4 expression by tumors may have an impact on prediction and evaluation of tumor response to therapies. In this study, we developed a robust and straightforward F-18 labeling route of T140, a CXCR4 peptide-based antagonist. PROCEDURES: T140 derivative was conjugated to 1,4,7-triazacyclononane-triacetic acid (NOTA) and labeled with Al[(18)F]. Al[(18)F]NOTA-T140 was evaluated in vitro in cell-based assay and stability in mouse serum and in vivo using CXCR4 positive and negative tumor xenograft models. RESULTS: Labeling of Al[(18)F]NOTA-T140 was completed within 30 min with a radiochemical yield of 58 ± 5.3 % at the end of synthesis, based on fluoride-18 activity. Al[(18)F]NOTA-T140 accumulated in CHO-CXCR4 positive but not negative tumors. Al[(18)F]NOTA-T140 uptake in the tumors correlated with CXCR4 protein expression. Moreover, Al[(18)F]NOTA-T140 had high accumulation in CXCR4-positive metastatic tumors. CONCLUSIONS: The simplicity of Al[(18)F]NOTA-T140 labeling along with its properties to specifically image CXCR4 expression by tumors warrant further clinical application for the diagnosis of CXCR4 clinically.