Air pollution and survival in patients with malignant mesothelioma and asbestos-related lung cancer: a follow-up study of 1591 patients in South Korea.

BACKGROUND: Despite significant advancements in treatments such as surgery, radiotherapy, and chemotherapy, the survival rate for patients with asbestos-related cancers remains low. Numerous studies have provided evidence suggesting that air pollution induces oxidative stress and inflammation, affecting acute respiratory diseases, lung cancer, and overall mortality. However, because of the high case fatality rate, there is limited knowledge regarding the effects of air pollution exposures on survival following a diagnosis of asbestos-related cancers. This study aimed to determine the effect of air pollution on the survival of patients with malignant mesothelioma and asbestos-related lung cancer. METHODS: We followed up with 593 patients with malignant mesothelioma and 998 patients with lung cancer identified as asbestos victims between 2009 and 2022. Data on five air pollutants-sulfur dioxide, carbon monoxide, nitrogen dioxide, fine particulate matter with a diameter < 10 µm, and fine particulate matter with a diameter < 2.5 µm-were obtained from nationwide atmospheric monitoring stations. Cox proportional hazard models were used to estimate the association of cumulative air pollutant exposure with patient mortality, while adjusting for potential confounders. Quantile-based g-computation was used to assess the combined effect of the air pollutant mixture on mortality. RESULTS: The 1-, 3-, and 5-year survival rates for both cancer types decreased with increasing exposure to all air pollutants. The estimated hazard ratios rose significantly with a 1-standard deviation increase in each pollutant exposure level. A quartile increase in the pollutant mixture was associated with a 1.99-fold increase in the risk of malignant mesothelioma-related mortality (95% confidence interval: 1.62, 2.44). For lung cancer, a quartile increase in the pollutant mixture triggered a 1.87-fold increase in the mortality risk (95% confidence interval: 1.53, 2.30). CONCLUSION: These findings support the hypothesis that air pollution exposure after an asbestos-related cancer diagnosis can negatively affect patient survival.

Development of finely tuned liposome nanoplatform for macrophage depletion.

BACKGROUND: Immunotherapy with clodronate-encapsulated liposomes, which induce macrophage depletion, has been studied extensively. However, previously reported liposomal formulation-based drugs (Clodrosome® and m-Clodrosome®) are limited by their inconsistent size and therapeutic efficacy. Thus, we aimed to achieve consistent therapeutic effects by effectively depleting macrophages with uniform-sized liposomes. RESULTS: We developed four types of click chemistry-based liposome nanoplatforms that were uniformly sized and encapsulated with clodronate, for effective macrophage depletion, followed by conjugation with Man-N3 and radiolabeling. Functionalization with Man-N3 improves the specific targeting of M2 macrophages, and radioisotope labeling enables in vivo imaging of the liposome nanoplatforms. The functionalized liposome nanoplatforms are stable under physiological conditions. The difference in the biodistribution of the four liposome nanoplatforms in vivo were recorded using positron emission tomography imaging. Among the four platforms, the clodronate-encapsulated mannosylated liposome effectively depleted M2 macrophages in the normal liver and tumor microenvironment ex vivo compared to that by Clodrosome® and m-Clodrosome®. CONCLUSION: The newly-developed liposome nanoplatform, with finely tuned size control, high in vivo stability, and excellent ex vivo M2 macrophage targeting and depletion effects, is a promising macrophage-depleting agent.

A Comparative Metagenomic Analysis of Specified Microorganisms in Groundwater for Non-Sterilized Pharmaceutical Products.

In pharmaceutical manufacturing, ensuring product safety involves the detection and identification of microorganisms with human pathogenic potential, including Burkholderia cepacia complex (BCC), Escherichia coli, Pseudomonas aeruginosa, Salmonella enterica, Staphylococcus aureus, Clostridium sporogenes, Candida albicans, and Mycoplasma spp., some of which may be missed or not identified by traditional culture-dependent methods. In this study, we employed a metagenomic approach to detect these taxa, avoiding the limitations of conventional cultivation methods. We assessed the groundwater microbiome's taxonomic and functional features from samples collected at two locations in the spring and summer. All datasets comprised 436-557 genera with Proteobacteria, Bacteroidota, Firmicutes, Actinobacteria, and Cyanobacteria accounting for > 95% of microbial DNA sequences. The aforementioned species constituted less than 18.3% of relative abundance. Escherichia and Salmonella were mainly detected in Hot Springs, relative to Jefferson, while Clostridium and Pseudomonas were mainly found in Jefferson relative to Hot Springs. Multidrug resistance efflux pumps and BlaR1 family regulatory sensor-transducer disambiguation dominated in Hot Springs and in Jefferson. These initial results provide insight into the detection of specified microorganisms and could constitute a framework for the establishment of comprehensive metagenomic analysis for the microbiological evaluation of pharmaceutical-grade water and other non-sterile pharmaceutical products, ensuring public safety.

Evaluation of PSMA target diagnostic PET tracers for therapeutic monitoring of [177Lu]ludotadipep of prostate cancer: Screening of PSMA target efficiency and biodistribution using [18F]DCFPyL and [68Ga]PSMA-11.

We have compared the similarity of the in vivo distribution of the prostate-specific membrane antigen (PSMA)-targeted positron emission tomography (PET) imaging agents [18F]DCFPyL, [68Ga]galdotadipep, and [68Ga]PSMA-11. This study is designed for a further selection of a PSMA-targeted PET imaging agent for the therapeutic evaluation of [177Lu]ludotadipep, our previously developed prostate-specific membrane antigen (PSMA)-targeted prostate cancer therapeutic radiopharmaceutical. In vitro cell uptake was performed to evaluate the affinity to PSMA using PSMA + PC3-PIP, and PSMA- PC3-flu was used for the study. MicroPET/CT 60 min dynamic imaging and biodistribution were performed at 1, 2, and 4 h after injection. Autoradiography and immunohistochemistry were performed to evaluate the PSMA + tumor target efficiency. In the microPET/CT image, [68Ga]PSMA-11 showed the highest uptake in the kidney among all three compounds. [18F]DCFPyL and [68Ga]PSMA-11 showed similar patterns of in vivo biodistribution and high tumor targeting efficiency, similar to those of[68Ga]galdotadipep. All three agents showed high uptake in tumor tissue on autoradiography, and PSMA expression was confirmed by immunohistochemistry. Thus, [18F]DCFPyL or [68Ga]PSMA-11 can be used as a PET imaging agent to monitor [177Lu]ludotadipep therapy in prostate cancer patients.

Early Prediction of Radiation-Induced Pulmonary Fibrosis Using Gastrin-Releasing Peptide Receptor-Targeted PET Imaging.

Early diagnosis of radiation-induced pulmonary fibrosis (RIPF) in lung cancer patients after radiation therapy is important. A gastrin-releasing peptide receptor (GRPR) mediates the inflammation and fibrosis after irradiation in mice lungs. Previously, our group synthesized a GRPR-targeted positron emission tomography (PET) imaging probe, [64Cu]Cu-NODAGA-galacto-bombesin (BBN), an analogue peptide of GRP. In this study, we evaluated the usefulness of [64Cu]Cu-NODAGA-galacto-BBN for the early prediction of RIPF. We prepared RIPF mice and acquired PET/CT images of [18F]F-FDG and [64Cu]Cu-NODAGA-galacto-BBN at 0, 2, 5, and 11 weeks after irradiation (n = 3-10). We confirmed that [64Cu]Cu-NODAGA-galacto-BBN targets GRPR in irradiated RAW 264.7 cells. In addition, we examined whether [64Cu]Cu-NODAGA-galacto-BBN monitors the therapeutic efficacy in RIPF mice (n = 4). As a result, the lung uptake ratio (irradiated-to-normal) of [64Cu]Cu-NODAGA-galacto-BBN was the highest at 2 weeks, followed by its decrease at 5 and 11 weeks after irradiation, which matched with the expression of GRPR and was more accurately predicted than [18F]F-FDG. These uptake results were also confirmed by the cell uptake assay. Furthermore, [64Cu]Cu-NODAGA-galacto-BBN could monitor the therapeutic efficacy of pirfenidone in RIPF mice. We conclude that [64Cu]Cu-NODAGA-galacto-BBN is a novel PET imaging probe for the early prediction of RIPF-targeting GRPR expressed during the inflammatory response.

Porphyrin-Based Brain Tumor-Targeting Agents: [64Cu]Cu-porphyrin and [64Cu]Cu-TDAP.

The aim of this study is to evaluate a radioactive metal complex platform for brain tumor targeting. Herein, we introduce a new porphyrin derivative, 5,10,15,20-(tetra-N,N-dimethyl-4-aminophenyl)porphyrin (TDAP), in which four N,N-dimethyl-4-p-phenylenediamine (DMPD) moieties are conjugated to the porphyrin labeled with the radiometal 64Cu. DMPD affected the pharmacokinetics of porphyrin in terms of retention time in vivo and tumor-targeting ability relative to those of unmodified porphyrin. [64Cu]Cu-TDAP showed stronger enhancement than [64Cu]Cu-porphyrin in U87MG glioblastoma cells, especially in the cytoplasm and nucleus, indicating its tumor-targeting properties and potential use as a therapeutic agent. In the subcutaneous and orthotopic models of brain-tumor-bearing mice, [64Cu]Cu-TDAP was clearly visualized in the tumor site via positron emission tomography imaging and showed a tumor-to-brain ratio as high as 13. [64Cu]Cu-TDAP deserves attention as a new diagnostic agent that is suitable for the early diagnosis and treatment of brain tumors.

Developmental complex trauma induces the dysfunction of the amygdala-mPFC circuit in the serotonergic and dopaminergic systems.

Developmental complex trauma is strongly associated with various psychiatric disorders in adulthood. Multiple lines of evidence have demonstrated that the amygdala-mPFC circuit regulates emotion and plays an important role in stress reactions. However, most studies on developmental trauma have mainly focused on neurological aspects in biological, behavioral, and structural changes with regard to a single stressor. In the present study, after applying complex stressors to the developmental phase, we would like to elucidate the functional changes in amygdala-mPFC circuit in the dopaminergic and serotonergic systems in the adult brain. Here, maternal separation and restraint stress were used to generate the trauma. The results showed that the body weights and corticosterone levels of animals exposed to developmental trauma decreased when compared to controls. In the neuroendocrine aspect, trauma leads to changes in proinflammatory cytokines, resulting in a decrease in IL-ß and an increase in TNF-α. In the neuroPET studies, the developmental trauma group displayed a reduction in serotonergic and dopaminergic PET uptake in the amygdala and mPFC. Collectively, our results indicate that developmental trauma weakens the serotonergic and dopaminergic systems in the amygdala-mPFC circuit.

Feasibility of Gd-Based prostate cancer targeted magnetic resonance agents using prostate specific membrane antigen.

The aim of this work was to evaluate Gd-FC705, a prostate-specific membrane antigen (PSMA)-targeted MRI contrast agent. The r1 and r2 relaxivities of Gd-FC705 are 5.94 mM-1s-1 and 17.77 mM-1s-1, respectively, in HSA solution (0.67 mM) at 3 T, which are higher than those of Gd-DOTA. Specific targeting efficacy was found with a 3-fold enhancement between PSMA-negative (PSMA-) and PSMA-positive (PSMA+) cells. The in vivo targeting and bio-distribution of Gd-FC705 were further confirmed using nude mice bearing PC3 human prostate cancer xenografts, which showed a 2-fold increase in the contrast-to-noise ratio (CNR) for PSMA+ tumors compared to PSMA- tumors 1 h post injection and a longer circulation time than Gd-DOTA. These results demonstrate that Gd-FC705 has great potential as a diagnostic agent for prostate cancer.

Physio-biochemical and molecular characterization of a rice drought-insensitive TILLING line 1 (ditl1) mutant.

Drought stress is a major abiotic stress that limits rice yield. Therefore, the development of new varieties tolerant to drought stress is a high priority in breeding programs. In this study, 150 rice M10 mutant lines, previously developed using gamma-ray irradiation, were used, and a drought-insensitive rice mutant (ditl1) was selected by drought stress screening. The ditl1 mutant exhibited significantly decreased water loss, leaf curling, and H2 O2 accumulation under drought stress. Chlorophyll leaching assay and toluidine blue staining suggested lower cuticle permeability in ditl1 mutants than in wild-type (WT) plants. In addition, transmission electron microscopy revealed that ditl1 plants accumulated more cuticular wax on the epidermal surface. Whole-genome resequencing analysis suggested that the deletion of a single nucleotide on the LOC_Os05g48260 gene, a putative ortholog of WSD1 (wax ester synthase/diacylglycerol O-acyltransferase in Arabidopsis), maybe be the gene responsible for the drought insensitive phenotype of ditl1. The ditl1 mutant will be a valuable breeding resource for developing drought stress tolerant rice cultivar.

In vivo evaluation of PEGylated-liposome encapsulating gadolinium complexes for gadolinium neutron capture therapy.

Gadolinium neutron capture therapy (GdNCT) is a form of binary radiotherapy. It utilizes nuclear reactions that occur when gadolinium-157 is irradiated with thermal neutrons, producing high-energy γ-rays and Auger electrons. Herein, we evaluate the potential of GdNCT for cancer treatment using PEGylated liposome incorporated with an FDA-approved MRI contrast agent. The clinical gadolinium complex (Gadovist®) was successfully encapsulated inside the aqueous core of PEGylated liposomes by repeated freeze and thaw cycling. At a concentration of 152 µM Gd, the Gd-liposome showed high cytotoxicity upon thermal-neutron irradiation. In animal experiments, when a CT26 tumor model was administered with Gd-liposomes (19 mg 157Gd per kg) followed by 20-min irradiation of thermal neutron at a flux of 1.94 × 104 cm-2 s-1, tumor growth was suppressed by 43%, compared to that in the control group, on the 23rd day of post-irradiation. After two-cycle GdNCT treatment at a 10-day interval, tumor growth was more efficiently retarded. On the 31st day after irradiation, the weight of the excised tumor in the GdNCT group (38 mg 157Gd per kg per injection) was only 30% of that of the control group. These results demonstrate the potential of GdNCT using PEGylated liposomes containing MRI contrast agents in cancer treatment.

Identification of genetic loci associated with major agronomic traits of wheat (Triticum aestivum L.) based on genome-wide association analysis.

BACKGROUND: Bread wheat (Triticum aestivum L.) is one of the most widely consumed cereal crops, but its complex genome makes it difficult to investigate the genetic effect on important agronomic traits. Genome-wide association (GWA) analysis is a useful method to identify genetic loci controlling complex phenotypic traits. With the RNA-sequencing based gene expression analysis, putative candidate genes governing important agronomic trait can be suggested and also molecular markers can be developed. RESULTS: We observed major quantitative agronomic traits of wheat; the winter survival rate (WSR), days to heading (DTH), days to maturity (DTM), stem length (SL), spike length (SPL), awn length (AL), liter weight (LW), thousand kernel weight (TKW), and the number of seeds per spike (SPS), of 287 wheat accessions from diverse country origins. A significant correlation was observed between the observed traits, and the wheat genotypes were divided into three subpopulations according to the population structure analysis. The best linear unbiased prediction (BLUP) values of the genotypic effect for each trait under different environments were predicted, and these were used for GWA analysis based on a mixed linear model (MLM). A total of 254 highly significant marker-trait associations (MTAs) were identified, and 28 candidate genes closely located to the significant markers were predicted by searching the wheat reference genome and RNAseq data. Further, it was shown that the phenotypic traits were significantly affected by the accumulation of favorable or unfavorable alleles. CONCLUSIONS: From this study, newly identified MTA and putative agronomically useful genes will help to study molecular mechanism of each phenotypic trait. Further, the agronomically favorable alleles found in this study can be used to develop wheats with superior agronomic traits.

Genome Wide Analysis of U-Box E3 Ubiquitin Ligases in Wheat (Triticum aestivum L.).

U-box E3 ligase genes play specific roles in protein degradation by post-translational modification in plant signaling pathways, developmental stages, and stress responses; however, little is known about U-box E3 genes in wheat. We identified 213 U-box E3 genes in wheat based on U-box and other functional domains in their genome sequences. The U-box E3 genes were distributed among 21 chromosomes and most showed high sequence homology with homoeologous U-box E3 genes. Synteny analysis of wheat U-box E3 genes was conducted with other plant species such as Brachypodium distachyon, barley, rice, Triricum uratu, and Aegilops tauschii. A total of 209 RNA-seq samples representing 22 tissue types, from grain, root, leaf, and spike samples across multiple time points, were analyzed for clustering of U-box E3 gene expression during developmental stages, and the genes responded differently in various tissues and developmental stages. In addition, expression analysis of U-box E3 genes under abiotic stress, including drought, heat, and both heat and drought, and cold conditions, was conducted to provide information on U-box E3 gene expression under specific stress conditions. This analysis of U-box E3 genes could provide valuable information to elucidate biological functions for a better understanding of U-box E3 genes in wheat.

Evaluation of the Effects of Developmental Trauma on Neurotransmitter Systems Using Functional Molecular Imaging.

Early life stress (ELS) is strongly associated with psychiatric disorders such as anxiety, depression, and schizophrenia in adulthood. To date, biological, behavioral, and structural aspects of ELS have been studied extensively, but their functional effects remain unclear. Here, we examined NeuroPET studies of dopaminergic, glutamatergic, and serotonergic systems in ELS animal models. Maternal separation and restraint stress were used to generate single or complex developmental trauma. Body weights of animals exposed to single trauma were similar to those of control animals; however, animals exposed to complex trauma exhibited loss of body weight when compared to controls. In behavioral tests, the complex developmental trauma group exhibited a decrease in time spent in the open arm of the elevated plus-maze and an increase in immobility time in the forced swim test when compared to control animals. In NeuroPET studies, the complex trauma group displayed a reduction in brain uptake values when compared to single trauma and control groups. Of neurotransmitter systems analyzed, the rate of decrease in brain uptake was the highest in the serotonergic group. Collectively, our results indicate that developmental trauma events induce behavioral deficits, including anxiety- and depressive-like phenotypes and dysfunction in neurotransmitter systems.

18 F-labeled 1,2,3-triazole-linked Glu-urea-Lys-based PSMA ligands have good pharmacokinetic properties for positron emission tomography imaging of prostate cancer.

BACKGROUND: Prostate-specific membrane antigen (PSMA) is increasingly recognized as an excellent target for prostate cancer imaging and therapy. Finding compounds with a high target-to-nontarget ratio are an important challenge in the development of positron emission tomography (PET) imaging agents. In this study, we attempted to find a suitable compound from a simply-synthesized compound library. METHOD: 18 F-labeling was achieved in a two-step synthesis consisting of [18 F]fluorination of azido sulfonates followed by copper(I)-catalyzed click ligation. In vitro binding experiment and in vivo studies were carried out using isogenic PSMA+ PC3-PIP and PSMA- PC3-flu cells and 22RV1 cells. [125 I]MIP-1095 was used to measure the binding affinities of compounds through a competitive binding assay, and [18 F]DCFPyL was used for a comparative assessment of compounds. Radiation dosimetry data were obtained using OLINDA/EXM software. RESULTS: Nine novel PSMA ligands were synthesized by the combination of three azido compounds and three terminal acetylene-containing Glu-urea-Lys compounds. Among them, compound 6f having a pyridine moiety showed a high binding affinity of 6.51 ± 0.19 nM (Ki ). 18 F-labeled compounds were obtained at moderate yields within 70 to 75 minutes (including high-performance liquid chromatography purification). Compound [18 F]6c had the lowest log P of -2.693. MicroPET/computed tomography (CT) images were acquired from 22RV1 cell xenograft mice after injecting [18 F]6c, [18 F]6f, and [18 F]6i. Additional microPET/CT experiments of [18 F]6c and [18 F]6f were performed using PSMA+ PC3-PIP and PSMA- PC3-flu cell-bearing mice. [18 F]6c was selected for further studies because it was found to have high uptake in tumors and rapid renal clearance, resulting in great tumor-to-nontumor ratios and distinct tumor images with very low background activity. Human dosimetry estimation of [18 F]6c using OLINDA/EXM software was calculated, resulting in an effective dose of 4.35 × 10-3 mSv/MBq. CONCLUSIONS: [18 F]6c showed significant tumor uptake, a high tumor-to-nontumor ratio, and good radiation dosimetry results, suggesting further development as a potential diagnostic PET agent for prostate cancer.

PEGylated liposome encapsulating nido-carborane showed significant tumor suppression in boron neutron capture therapy (BNCT).

Boron neutron capture therapy (BNCT) is a binary radiotherapy based on nuclear reactions that occur when boron-10 is irradiated with neutrons, which result in the ejection of high-energy alpha particles. Successful BNCT requires the efficient delivery of a boron-containing compound to effect high concentrations in tumor cells while minimizing uptake in normal tissues. In this study, PEGylated liposomes were employed as boron carriers to maximize delivery to tumors and minimize uptake in the reticuloendothelial system (RES). The water-soluble potassium salt of nido-7,8-carborane, nido-carborane, was chosen as the boron source due to its high boron content per molecule. Nido-carborane was encapsulated in the aqueous cores of PEGylated liposomes by hydrating thin lipid films. Repeated freezing and thawing increased nido-carborane loading by up to 47.5 ± 3.1%. The average hydrodynamic diameter of the prepared boronated liposomes was determined to be 114.5 ± 28 nm through dynamic light scattering (DLS) measurement. Globular liposomes approximately 100 nm in diameter were clearly visible in transmission electron microscope (TEM) images. The viability of tumor cells following BNCT with 70 µM nido-carborane was reduced to 17.1% compared to irradiated control cells, which did not contain boronated liposomes. Confocal microscopy revealed that fluorescently labeled liposomes injected into the tail veins of mice were deeply and evenly distributed in tumor tissues and localized in the cytoplasm of tumor cells. When mice were properly shielded with a 12 mm-thick polyethylene board during in-vivo irradiation at a thermal neutron flux of 1.94 × 104/cm2·sec, almost complete tumor suppression was achieved in tumor models injected with boronated liposomes (21.0 mg 10B/kg). Two BNCT cycles spaced 10 days apart further enhanced the therapeutic anti-tumor effect, even when the dose was lowered to 10.5 mg 10B/kg. No notable weight loss was observed in the tumor models during the BNCT study.

A comparison of culture-based, real-time PCR, droplet digital PCR and flow cytometric methods for the detection of Burkholderia cepacia complex in nuclease-free water and antiseptics.

The presence of Burkholderia cepacia complex (BCC) strains has resulted in recalls of pharmaceutical products, since these opportunistic pathogens can cause serious infections. Rapid and sensitive diagnostic methods to detect BCC are crucial to determine contamination levels. We evaluated bacterial cultures, real-time PCR (qPCR), droplet digital PCR (ddPCR), and flow cytometry to detect BCC in nuclease-free water, in chlorhexidine gluconate (CHX) and benzalkonium chloride (BZK) solutions. Twenty BCC strains were each suspended (1, 10, 100, and 1000 CFU/ml) in autoclaved nuclease-free water, 10 µg/ml CHX, and 50 µg/ml BZK. Five replicates of each strain were tested at each concentration (20 strains × 4 concentrations × 5 replicates = 400 tests) to detect BCC using the aforementioned four methods. We demonstrated the potential of ddPCR and flow cytometry as more sensitive alternatives to culture-based methods to detect BCC in autoclaved nuclease-free water and antiseptics samples.

Ionizing radiation attracts tumor targeting and apoptosis by radiotropic lysyl oxidase traceable nanoparticles.

Lysyl oxidase (LOX) is a cell-secreted amine oxidase that crosslinks collagen and elastin in extracellular microenvironment. LOX-traceable nanoparticles (LOXab-NPs) consisting of LOX antibodies (LOXab) and paclitaxel, can accumulate at high concentrations at radiation-treated target sites, as a tumor-targeting drug carrier for chemotherapy. Tumor-targeting and anticancer effects of PLGA based LOXab-NPs in vitro and in vivo were evaluated at radiation-targeted site. In the in vivo A549 lung carcinoma xenograft model, we showed highly specific tumor targeting (above 7.0 times higher) of LOXab-NPs on irradiated tumors. Notably, systemically administered NPs delayed tumor growth, reducing tumor volumes by more than 2 times compared with non-irradiated groups (222% vs. >500%) over 2 weeks. Radiotropic LOXab-NPs can serve as chemotherapeutic vehicles for combined targeted chemo-radiotherapy in clinical oncology.

Effects of P-gp and Bcrp as brain efflux transporters on the uptake of [18 F]FPEB in the murine brain.

The purpose of this study was to determine whether the brain uptake of [18 F]FPEB is influenced by P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp) as efflux transporters in rodents. To assess this possible modulation, positron emission tomography studies were performed in animal models of pharmacological or genetic ablation of these transporters. Compared with the control conditions, when P-gp was blocked with tariquidar, there was an 8%-12% increase in the brain uptake of [18 F]FPEB. In P-gp knockout mice, such as Mdr1a/b(-/-) and Mdr1a/b(-/-) Bcrp1(-/-) , genetic ablation models, there was an increment of 8%-53% in [18 F]FPEB uptake compared with that in the wild-type mice. In contrast, Bcrp knockout mice showed a decrement of 5%-12% uptake and P-gp/Bcrp knockout group displayed an increment of 5%-17% compared with wild type. These results indicate that [18 F]FPEB is possibly a weak substrate for P-gp.

Combination Radioimmunotherapy Strategies for Solid Tumors.

Combination radioimmunotherapy is an emerging approach for the treatment of solid tumors where radio immunotherapy alone has proven to be reasonably ineffective. Radioimmunotherapy (RIT) using monoclonal antibodies (mAbs) labeled with radionuclides is an attractive approach for cancer treatment because tumor-associated mAbs with cytotoxic radionuclides can selectively bind to tumor antigens. However, due to various limitations, mAbs cannot reach solid tumors, consequently reducing RIT efficacy. Combination RIT is a pragmatic approach through which the addition of drugs or other agents not only help mAbs to reach the targeted site but also improves its efficacy. Thus, the combination of drugs or moieties with RIT can be applied to overcome the barriers that RIT faces for solid tumors. This review covers the RIT approach, along with the mechanism of action of mAb used in RIT, limitations of solid tumors, and strategies that can be used in combination RIT to enhance the treatment regimen for solid tumors.

Comparison between Fractionated Dose and Single Dose of Cu-64 Trastuzumab Therapy in the NCI-N87 Gastric Cancer Mouse Model.

For optimum radioimmunotherapy (RIT), deep penetration and uniform distribution into the tumor core is important. The solid tumor microenvironment, consisting of a highly fibrotic or desmoplastic tumor, abnormal tumor vasculature, high fluid pressure, and the absence of fluid lymphatics, limits the distribution of monoclonal antibodies mAbs to the tumor core. To investigate the optimal rationale for therapeutic mAbs administration and the microdistribution of mAbs, single and serial fractional dosage regimens of Cu-64-trastuzumab (TRZ) with paclitaxel were evaluated. Groups of nude mice were inoculated with gastric cancer cell line NCI-N87 tumor cells. When the tumor size reached 200 ± 20 mm3, the mice were divided into two groups for injection of Alexa-647-TRZ. One group (n = 5) was injected with 15 mg/kg in a single dose (SD), and the other group (n = 5) with two doses of 7.5 mg/kg (fractionated dose (FD)). In both cases, the injections were done intravenously in combination with intraperitoneal paclitaxel either as a SD of 70 mg/kg or fractionated into two doses of 40 and 30 mg/kg. Tumors were harvested, flash frozen, and sectioned (8 µm) five days after Alexa-647-TRZ injection. Rhodamine lectin (rhodamine-labeled Ricinus communis agglutinin I, 1 mg in 0.2 mL of phosphate-buffered saline (PBS)) was intravenously injected to delineate the functional vessel for a wait time of 5 min before animal euthanization. Microscopic images were acquired with an IN Cell Analyzer. The amount of TRZ that penetrated the tumor surface and the tumor vessel was calculated by area under the curve (AUC) analysis. For RIT efficacy (n = 21), Cu-64-TRZ was injected following the same dose schedule to observe tumor volume and survival ratio for 30 days. The SD and FD regimens of Alexa-647-TRZ were observed to have no significant difference in penetration of mAbs from the tumor edge and vessel, nor was the total accumulation across the whole tumor tissue significantly different. Additionally, the SD and FD regimens of Cu-64-TRZ were not proven to be significantly efficacious. Our study reveals that SD and FD in a treatment design with Cu-64-TRZ and paclitaxel shows no significant difference in therapeutic efficacy on tumor growth inhibition in vivo in mice bearing human gastric cancer xenografts overexpressing HER2 antigen.