Carborane-FAPI conjugate: A potential FAP-targeted boron agent with improved boron content.

Boron neutron capture therapy (BNCT) has received extensive attention as an advanced binary radiotherapy method. However, BNCT still faces poor selectivity of boron agent and is insufficient boron content in tumor tissues. To improve the tumor-targeted ability and boron content, this research aims to design, synthesize and preliminary evaluate a new borane agent Carborane-FAPI, which coupling the o-carborane to the compound skeleton of a mature fibroblast activating protein (FAP) inhibitor (FAPI). FAP is a tumor-associated antigen. FAP expressed lowly in normal organs and highly expressed in tumors, so it is a potential target for diagnosis and treatment. Boronophenylalanine (BPA) is the most widely investigated BNCT drug in present. Compared with BPA, the boron content of a single molecule is increased and drug targeting is enhanced. The results show that Carboaren-FAPI has low toxicity to normal cells, and selective enrichment in tumor tissues. It is a promising boron drug that has the potential to be used in BNCT.

Fluorine-18 labeling PEGylated 6-boronotryptophan for PET scanning of mice for assessing the pharmacokinetics for boron neutron capture therapy of brain tumors.

Two tryptophan compound classes 5- and 6-borono PEGylated boronotryptophan derivatives have been prepared for assessing their aqueous solubility as formulation of injections for boron neutron capture therapy (BNCT). The PEGylation has improved their aqueous solubility thereby increasing their test concentration in 1 mM without suffering from toxicity. In-vitro uptake assay of PEGylated 5- and 6-boronotryptophan showed that the B-10 concentration can reach 15-50 ppm in U87 cell whereas the uptake in LN229 cell varies. Shorter PEG compound 6-boronotryptophanPEG200[18F] was obtained in 1.7 % radiochemical yield and the PET-derived radioradioactivity percentage in 18 % was taken up by U87 tumor at the limb of xenograft mouse. As high as tumor to normal uptake ratio in 170 (T/N) was obtained while an inferior radioactivity uptake of 3 % and T/N of 8 was observed in LN229 xenografted mouse.

A bis-boron boramino acid PET tracer for brain tumor diagnosis.

PURPOSE: Boramino acids are a class of amino acid biomimics that replace the carboxylate group with trifluoroborate and can achieve the 18F-labeled positron emission tomography (PET) and boron neutron capture therapy (BNCT) with identical chemical structure. METHODS: This study reports a trifluoroborate-derived boronophenylalanine (BBPA), a derived boronophenylalanine (BPA) for BNCT, as a promising PET tracer for tumor imaging. RESULTS: Competition inhibition assays in cancer cells suggested the cell accumulation of [18F]BBPA is through large neutral amino acid transporter type-1 (LAT-1). Of note, [18F]BBPA is a pan-cancer probe that shows notable tumor uptake in B16-F10 tumor-bearing mice. In the patients with gliomas and metastatic brain tumors, [18F]BBPA-PET shows good tumor uptake and notable tumor-to-normal brain ratio (T/N ratio, 18.7 ± 5.5, n = 11), higher than common amino acid PET tracers. The [18F]BBPA-PET quantitative parameters exhibited no difference in diverse contrast-enhanced status (P = 0.115-0.687) suggesting the [18F]BBPA uptake was independent from MRI contrast-enhancement. CONCLUSION: This study outlines a clinical trial with [18F]BBPA to achieve higher tumor-specific accumulation for PET, provides a potential technique for brain tumor diagnosis, and might facilitate the BNCT of brain tumors.

Fluorinated borono-phenylalanine for optimizing BNCT: Enhancing boron absorption against hydrogen scattering for thermal neutrons.

BACKGROUND: Boron-containing compounds, such as 4-borono-phenylalanine (BPA) are used as drugs for cancer treatment in the framework of Boron Neutron Capture Therapy (BNCT). Neutron irradiation of boron-rich compounds delivered to cancer cells triggers nuclear reactions that destroy cancer cells. PURPOSE: We provide a modeling of the thermal neutron cross section of BPA, a drug used in Boron Neutron Capture Therapy (BNCT), to quantify the competing contributions of boron absorption against hydrogen scattering, for optimizing BNCT by minimizing the latter. METHODS: We perform the experimental determination of the total neutron scattering cross section of BPA at thermal and epithermal neutron energies using neutron transmission measurements. We isolate the contribution related to the incoherent scattering by hydrogen atoms as a function of the neutron energy by means of the Average Functional Group Approximation, and we calculate the probability for a neutron of being absorbed as a function of the neutron energy both for BPA and for its variants where either one or all four aromatic hydrogen atoms are substituted by 19 F, and both for the samples with natural occurrence or enriched concentration of 10 B. RESULTS: While referring to the already available literature for in vivo use of fluorinated BPA, we show that fluorine-rich variants of BPA increase the probability of neutrons being captured by the molecule. As the higher absorption efficiency of fluorinated BPA does not depend on whether the molecule is used in vivo or not, our results are promising for the higher efficiency of the boron neutron capture treatment. CONCLUSIONS: Our results suggest a new advantage using fluorinated compounds for BNCT, in their optimized interaction with neutrons, in addition to their already known capability to be used for monitoring and pharmacokinetics studies using 19 F-Nuclear Magnetic Resonance or in 18 F-Positron Emission Tomography.

Boron Neutron Capture Therapy (BNCT) for Cutaneous Malignant Melanoma Using 10B-p-Boronophenylalanine (BPA) with Special Reference to the Radiobiological Basis and Clinical Results.

BNCT is a radiotherapeutic method for cancer treatment that uses tumor-targeting 10B-compounds. BNCT for cutaneous melanoma using BPA, a phenylalanine derivative, was first initiated by Mishima et al. in 1987. This article reviews the radiobiological basis of melanoma control and damage to normal tissues as well as the results of clinical studies. Experimental studies showed that the compound biological effectiveness (CBE) values of the 10B (n, α)7Li reaction for melanoma control ranged from 2.5 to 3.3. The CBE values of the 10B (n, α)7Li reaction for skin damage ranged from 2.4 to 3.7 with moist desquamation as the endpoint. The required single radiation dose for controlling human melanoma was estimated to be 25 Gy-Eq or more by analyzing the 50% tumor control dose data of conventional fractionated radiotherapy. From the literature, the maximum permissible dose to human skin by single irradiation was estimated to be 18 Gy-Eq. With respect to the pharmacokinetics of BPA in patients with melanoma treated with 85-350 mg/kg BPA, the melanoma-to-blood ratio ranged from 2.1-3.8 and the skin-to-blood ratio was 1.31 ± 0.22. Good local tumor control and long-term survival of the patients were achieved in two clinical trials of BNCT conducted in Japan.

Pharmacology differences among proteasome inhibitors: Implications for their use in clinical practice.

Preclinical and clinical investigation on proteasome as a druggable target in cancer has led to the development of proteasome inhibitors (PIs) with different pharmacodynamic and pharmacokinetic properties. For example, carfilzomib has a better safety profile and a lower risk of clinically relevant drug-drug interactions than bortezomib, whereas ixazomib can be orally administered on a weekly basis due to a very long elimination half-life and high systemic exposure. The purpose of this review article is to elucidate the quantitative and qualitative differences in potency, selectivity, pharmacokinetics, safety and drug-drug interactions of clinically validated PIs to provide useful information for their clinical use in real life setting.

Highly stable organic photothermal agent based on near-infrared-II fluorophores for tumor treatment.

BACKGROUND: The aim to develop a highly stable near-infrared (NIR) photoinduced tumor therapy agent stems from its considerable potential for biological application. Due to its long wavelength, biological imaging exhibits a high signal-to-background ratio, deep tissue penetration and maximum permissible light power, which can minimize damage to an organism during photoinduced tumor therapy. RESULTS: A class of stable NIR-II fluorophores (NIR998, NIR1028, NIR980, NIR1030, and NIR1028-S) based on aza-boron-dipyrromethene (aza-BODIPY) dyes with donor-acceptor-donor structures have been rationally designed and synthesized by harnessing the steric relaxation effect and intramolecular photoinduced electron transfer (IPET). These fluorophores exhibit an intense range of NIR-II emission, large Stokes shift (≥ 100 nm), excellent photothermal conversion performance, and superior stability against photobleaching. Among the NIR-II fluorophores, NIR998 possesses better NIR-II emission and photothermal conversion performance. NIR998 nanoparticles (NIR998 NPs) can be encapsulated by liposomes. NIR998 NPs show superior stability in the presence of light, heat, and reactive oxygen nitrogen species than that of indocyanine green NPs, as well as a higher photothermal conversion ability (η = 50.5%) compared to other photothermal agents. Finally, under the guidance of photothermal imaging, NIR998 NPs have been proven to effectively eliminate tumors via their excellent photothermal conversion performance while presenting negligible cytotoxicity. CONCLUSIONS: Utilizing IPET and the steric relaxation effect can effectively induce NIR-II emission of aza-BODIPY dyes. Stable NIR998 NPs have excellent photothermal conversion performance and negligible dark cytotoxicity, so they have the potential to act as photothermal agents in biological applications.

Studying Adsorption and Cellular Toxicity of Boron Nitride Nanostructure versus Melphalan Anti-ovarian Cancer Drug.

BACKGROUND: Inclusion of anticancer drugs into biocompatible nanoparticulate carriers decreases the general toxicity and improves the efficacy of clinical treatments due to the reduction of soluble circulating free drugs. METHODS: In addition, removal of emerging drug contaminants from wastewaters is a necessity that should be seriously attended. Boron nitride (BN) is a choice in drug delivery because of its many surprising properties. Here, boron nitride nanoparticles are prepared, characterized by Fourier-transform infrared spectroscopy (FT-IR) and x-ray diffraction (XRD) and used in the delivery of melphalan anti-cancer drug. RESULTS: Then, density functional theory (DFT) calculations are carried out to study the adsorption of this drug on the surface of pure boron nitride fullerene via familiar hybrid functionals B3LYP and B3PW91. In addition, the polarizable continuum model (PCM) calculations show that BN is stable in water. CONCLUSION: Finally, the in vitro cellular toxicity and viability of BN nanoparticles was examined on ES-2 cancer cells. The inhibitory dose IC50 of the material confirmed acceptable cytotoxicity and nanoparticles affected the average growth of the ES-2 cancer cells.

Pharmacokinetics of 10B-p-boronophenylalanine (BPA) in the blood and tumors in human patients: A critical review with special reference to tumor-to-blood (T/B) ratios using resected tumor samples.

We reviewed 10B concentration kinetics in the blood and tumors in human patients administered with BPA. The 10B concentration in the blood peaked at the end of intravenous infusion of BPA, followed by a biphasic-decreasing curve with half-lives for the first and second components of the curve being 0.7-3.7 and 7.2-12.0 h, respectively. The mean tumor-to-blood (T/B) ratio obtained from resected tumor samples was 3.40 ± 0.83 for melanoma and the ratio ranged from 1.4 to 4.7 for glioblastoma.

Effects of curcumin complexes on MDA­MB­231 breast cancer cell proliferation.

Curcumin displays anticancer properties; however, some issues with the drug delivery mode limit its therapeutic use. Although reformulation and derivatization of curcumin have improved its bioavailability, curcumin derivatives may not retain the same anticancer properties as the parent compound. The present study investigated the anticancer properties of two curcumin complexes, the iron­curcumin [Fe(Cur)3] and boron­curcumin [B(Cur)2] complexes, in the MDA­MB­231 breast cancer cell line. The cellular localization of curcumin, B(Cur)2 and Fe(Cur)3 was determined by fluorescence microscopy. Cell proliferation, migration and invasion were also analysed. Furthermore, apoptosis­associated proteins were detected by using a proteome profiler array, and ion channel gene expression was analysed by reverse transcription­quantitative PCR. The results demonstrated that the three compounds were localized in the perinuclear and cytoplasmic regions of the cell, and displayed cytotoxicity with IC50 values of 25, 35 and 8 µM for curcumin, B(Cur)2 and Fe(Cur)3, respectively. In addition, the three compounds inhibited cell invasion, whereas only curcumin and B(Cur)2 inhibited cell migration. Furthermore, cell exposure to curcumin resulted in an increase in the relative expression of the two key proapoptotic proteins, cytochrome c and cleaved caspase­3, as well as the antiapoptotic protein haem oxygenase­1. In addition, curcumin increased the expression levels of the voltage­gated potassium channels Kv2.1 and Kv3.2. Similarly, the expression levels of the chloride channel bestrophin­1 and the calcium channel coding gene calcium voltage­gated channel auxiliary subunit γ4 were increased following exposure to curcumin. Taken together, these results indicated that Fe(Cur)3 and B(Cur)2 may display similar anticancer properties as curcumin, suggesting that chemical complexation may be considered as a strategy for improving the potency of curcumin in the treatment of breast cancer.

Difference in BPA uptake between glioma stem-like cells and their cancerous cells.

Tumor sphere-forming (TS) glioma stem cells and cancerous TS cells were analyzed in vivo and in vitro. The boron concentration in murine TS tumors was higher than normal tissue. The boron concentration at 24 h was 0.80 ± 0.09 µg/107 in the TS cells, and 1.08 ± 0.08 µg/107 in the cancerous cells. The LAT-1 amino-acid transporter positive rate was 35.4% in the TS cells and 100% in the cancerous cells. These results suggested the relation between LAT-1 expression and boronophenylalanine concentration in vitro.

Predictors of Systemic Exposure to Topical Crisaborole: A Nonlinear Regression Analysis.

Crisaborole ointment, 2%, is a nonsteroidal phosphodiesterase 4 inhibitor for the treatment of mild to moderate atopic dermatitis. Results from 2 randomized, double-blind, vehicle-controlled phase 3 studies showed that twice-daily crisaborole in children and adults with mild to moderate atopic dermatitis was efficacious and well tolerated. Initial pharmacokinetics (PK) studies of crisaborole indicated absorption with measurable systemic levels of crisaborole. The current analysis was conducted to correlate steady-state systemic exposure parameters with ointment dose and identify covariates impacting PK parameters in healthy participants and patients with atopic dermatitis or psoriasis. A nonlinear regression analysis was conducted using ointment dose and noncompartmental PK parameters at steady state (area under the curve [AUCss ] and maximum concentration [Cmax,ss ]). PK data were available from 244 participants across 6 clinical studies (AUCss , N = 239; Cmax,ss , N = 241). Disease condition had the greatest impact on slope in both models, corresponding to 2.5-fold higher AUCss and Cmax,ss values at a given ointment dose in patients with atopic dermatitis or psoriasis relative to healthy participants. Disease severity, race/ethnicity, and sex had marginal effects on AUCss and Cmax,ss . Systemic exposures were similar across age groups ≥2 years of age when the same percentage of body surface area (%BSA) was treated. Predictive performance plots for AUCss and Cmax,ss for different age groups demonstrated that the models adequately describe the observed data. Model predictions indicated that systemic exposure to crisaborole in pediatric patients (2-17 years) is unlikely to exceed systemic exposure in adults (≥18 years), even at the highest possible ointment dose corresponding to a %BSA of 90.

Safety, Effectiveness, and Pharmacokinetics of Crisaborole in Infants Aged 3 to < 24 Months with Mild-to-Moderate Atopic Dermatitis: A Phase IV Open-Label Study (CrisADe CARE 1).

BACKGROUND: Crisaborole ointment, 2%, is a nonsteroidal phosphodiesterase 4 inhibitor for the treatment of mild-to-moderate atopic dermatitis (AD). OBJECTIVES: The aim of this study was to evaluate the safety, effectiveness, and pharmacokinetics (PK) of crisaborole in infants aged 3 to < 24 months with mild-to-moderate AD in an open-label study. METHODS: Infants (3 to < 24 months) with Investigator's Static Global Assessment (ISGA) of mild (2) or moderate (3) and percentage of treatable body surface area (%BSA) ≥ 5 received crisaborole twice daily for 28 days; a cohort with moderate AD per ISGA and %BSA ≥ 35 were included in a PK analysis. Endpoints included safety (primary), efficacy, and PK (exploratory). RESULTS: Included were 137 infants total (mean age [SD], 13.6 months [6.42]), with 21 in the PK cohort (12.7 months [6.58]). Treatment-emergent adverse events (TEAEs) were reported for 88 (64.2%) patients (98.9% rated as mild/moderate). TEAEs were considered treatment-related for 22 patients (16.1%); most frequently reported were application site pain (3.6%), application site discomfort (2.9%), and erythema (2.9%). ISGA clear/almost clear with ≥ 2-grade improvement at day 29 was achieved by 30.2% of patients. From baseline to day 29, mean percentage change in Eczema Area and Severity Index score was - 57.5%, and mean change in Patient-Oriented Eczema Measure total score was - 8.5. Crisaborole systemic exposures in infants were characterized and, based on nonlinear regression analysis, were comparable with that in patients aged ≥ 2 years. CONCLUSIONS: In this open-label study, crisaborole was well tolerated and effective in infants (3 to < 24 months) with mild-to-moderate AD with systemic exposures similar to patients aged ≥ 2 years. CLINICAL TRIAL REGISTRATION: NCT03356977.

Atopic dermatitis (AD) is a skin disease that causes inflamed and itchy skin. Crisaborole is an ointment that is approved to treat patients aged 2 years and older with mild-to-moderate AD. This clinical trial studied crisaborole in infants with mild-to-moderate AD who were 3 to under 24 months old. These infants were treated with crisaborole twice a day for 28 days. The trial studied crisaborole's safety, effectiveness, and absorption into the bloodstream. In total, 137 infants were treated. Although side effects of some sort occurred in about two-thirds of patients, only 1 in 6 patients experienced side effects that were attributed to crisaborole. When these side effects did occur, these were mainly pain, discomfort, or redness where crisaborole was applied. Fewer than 1 in 25 patients experienced each side effect where crisaborole was applied. The doctors saw improvement in the AD symptoms of some patients at day 29 of the study compared to the beginning of the study. Crisaborole blood-level measurements in this age group were consistent with those seen in patients aged 2 years and older. Overall, crisaborole was considered well tolerated and effective in infants (3 to under 24 months old) with mild-to-moderate AD. Safety, Effectiveness, and Pharmacokinetics of Crisaborole in Infants Aged 3 to < 24 Months with Mild-to-Moderate Atopic Dermatitis: An Open-Label, Phase 4 Study (MP4 40891 MB).

A diaminomaleonitrile-appended BODIPY chemosensor for the selective detection of Cu2+ via oxidative cyclization and imaging in SiHa cells and zebrafish.

A specific Cu2+ sensor, 2-amino-3-(BODIPYmethyleneamino)maleonitrile (BDM), was established by a simple dehydration between BODIPY and diaminomaleonitrile. Cu2+ could be recognized by BDM over other competing metal ions in acetonitrile with distinct fluorescence emission signal response. Upon the addition of Cu2+ to BDM in acetonitrile, the maximum absorption at approximately 530 nm on the longer wavelength side was quenched, and the emission at 530 nm was ignited simultaneously. The fluorescence intensity enhancement could reach a maximum of 204 times the intensity of the BDM blank solution. The fluorescence "off-on" effect is established according to the Cu2+-induced fast intramolecular oxidative cyclization reaction, which could be deduced from the formation of an imidazole ring appended to the cyclization product (2-BODIPY-1H-imidazole-4,5-dicarbonitrile, BMC). Single-crystal structure analysis of the sensor BDM and cyclization product BMC further demonstrated this oxidative cyclization. Finally, the Cu2+ recognition property of BDM was validated in SiHa cells and living zebrafish. Additionally, the blood-brain barrier of the zebrafish can be penetrated by the BDM dye and the neuron cells in the brain were stained.

Active targeted ligand-aza-BODIPY conjugate for near-infrared photodynamic therapy in melanoma.

Active targeting compound, a non-iodinated derivative of IK-IK-I2-azaBODIPY (1a) was previously reported to preferentially bind melanoma over healthy cells. In this study, we evaluate the photodynamic therapy (PDT) efficiency on melanoma cells of 1a, together with its reversed sequence compound KI-KI-I2-azaBODIPY (1b) and a non-targeted control I2-azaBODIPY-NH2 (2). All three test compounds possess absorption wavelengths in the near-infrared (NIR) region (λmax between 678 and 687 nm) which alleviate melanin interference and allow deeper tissue penetration. In vitro studies revealed 1a and 1b are promising photosensitizers with enhanced singlet oxygen generation, have increased uptake by B16-F10 melanoma cells via clathrin-mediated endocytosis and good photocytotoxic efficacies. Ex vivo biodistribution assays showed both 1a and 1b accumulated in the tumour. In B16-F10 tumour bearing-C57BL/6 mice, 10 mg/kg of 1b and light irradiation was found to reduce tumour volume by up to 23% at day-3. Doubling the dosage of 1b (20 mg/kg) enhanced the antitumour effect, showing 96% maximum tumour volume reduction at day-7 and tumour growth suppression for up to 12 days.

Poly(vinyl alcohol) boosting therapeutic potential of p-boronophenylalanine in neutron capture therapy by modulating metabolism.

In the current clinical boron neutron capture therapy (BNCT), p-boronophenylalanine (BPA) has been the most powerful drug owing to its ability to accumulate selectively within cancers through cancer-related amino acid transporters including LAT1. However, the therapeutic success of BPA has been sometimes compromised by its unfavorable efflux from cytosol due to their antiport mechanism. Here, we report that poly(vinyl alcohol) (PVA) can form complexes with BPA through reversible boronate esters in aqueous solution, and the complex termed PVA-BPA can be internalized into cancer cells through LAT1-mediated endocytosis, thereby enhancing cellular uptake and slowing the untoward efflux. In in vivo study, compared with clinically used fructose-BPA complexes, PVA-BPA exhibited efficient tumor accumulation and prolonged tumor retention with quick clearance from bloodstream and normal organs. Ultimately, PVA-BPA showed critically enhanced antitumor activity in BNCT. The facile technique proposed in this study offers an approach for drug delivery focusing on drug metabolism.

Comparative Study on Neutron Irradiation Sensitization Effects of Nucleotide Borate Esters and Several Other Boron Agents.

More effective boron-containing compounds are needed for use in boron neutron capture therapy (BNCT). Here, borate esters were synthesized by heating and dehydrating nucleotides adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine monophosphate (AMP), the nucleoside (inosine) or glycerol in the presence of boric acid (H3BO3). Borate ester products were compared to clinical boron agent boronophenylalanine (BPA) and several other borate esters for neutron-sensitization effects using the A549 cell line. Cells were incubated with boron agent solutions (2.3 mM) for 5 h, then washed, resuspended in fresh media, and irradiated with a neutron dose of 0.33 Sv followed by cell survival assessment using the CCK-8 method. Calculated radiosensitization values (control group cell survival rate/boron agent-treated experimental group cell survival rate) were 3.9 ± 0.2 (ATP borate ester), 2.4 ± 0.1 (BPA), 2.1 ± 0.1 (ADP borate ester), 1.9 ± 0.2 (AMP borate ester), 1.7 ± 0.3 (glycerin borate ester), 1.4 ± 0.1 (inosine borate ester), 1.3 ± 0.3 (triethanolamine borate ester) and 1.3 ± 0.5 (H3BO3). Borate esters derived from nucleotides ATP, ADP or AMP exhibited significantly higher sensitization values than did those derived from glycerol, inosine or triethanolamine. Notably, due to its relatively higher water solubility and degree of tumor cell enrichment, ATP borate ester exhibited the highest sensitization rate overall, significantly exceeding rates obtained for BPA and borate esters of ADP and AMP. Flow cytometric determinations of boron agent-treated cell survival at 24 h postirradiation revealed long-term apoptosis rates of 4.8-6.6 ± 0.2% (nucleotide borate ester groups) and 5.6 ± 0.3% (BPA group) compared to 3.9 ± 0.1% (irradiation control group without boron agent) and 2.6 ± 0.2% (blank control group). Significant differences between experimental and control groups demonstrated that nucleotide borate esters and BPA induced long-term radiosensitization effects. In particular, postirradiation percentages of ATP borate ester-treated cells progressing to DNA replication prophase (G1 phase) increased significantly, while percentages of cells progressing to S phase significantly decreased, demonstrating cellular DNA replication inhibition. Meanwhile, boron content values of tumor tissue, measured using inductively coupled plasma mass spectrometry (ICP-MS) and expressed as tumor-to-normal tissue boron ratios (T/N), were not significantly different between nucleotide borate ester- and BPA-fed groups of tumor-bearing mice. However, tumor tissue boron concentrations of nucleotide borate ester-fed mice (0.81-0.88 ± 0.04 µg/g) significantly exceeded those of BPA-fed mice (0.52 ± 0.05 µg/g) and thus provided greater tumor tissue boron enrichment for achieving a stronger neutron radiation-sensitizing effect. In conclusion, nucleotide borate esters, especially ATP borate ester, exhibited superior neutron radiosensitization effects than did other representative borate ester compounds and significantly greater long-term radiation effects as well. Thus, nucleotide borate esters have several advantages over other borate esters for BNCT and therefore warrant further study.

Phase 1 study of crisaborole in Japanese healthy volunteers and patients with atopic dermatitis.

Crisaborole ointment, 2%, is a non-steroidal phosphodiesterase 4 inhibitor for the treatment of mild to moderate atopic dermatitis (AD). This parallel-cohort, phase 1 study was conducted to investigate skin irritation potential and safety of crisaborole in healthy Japanese adults (cohort 1) and the safety and pharmacokinetic profile of crisaborole and metabolites AN7602 and AN8323 in Japanese adults with mild to moderate AD (cohort 2). In cohort 1, 20 healthy volunteers received single applications of crisaborole and vehicle simultaneously on separate locations under 48-h occlusion. In cohort 2, 12 patients with mild to moderate AD received crisaborole (n = 10) or vehicle (n = 2) twice daily for 8 days. Skin irritation and safety were assessed in cohort 1. Pharmacokinetics and safety were assessed in cohort 2. Skin irritation index (scale 0-400) was 40.0 for crisaborole and 5.0 for vehicle. No treatment-emergent adverse events (TEAE) were reported in cohort 1. The most common TEAE in the crisaborole group in cohort 2 were application site irritation (n = 7) and application site pain (n = 4). Crisaborole was rapidly absorbed, with limited systemic exposure between days 1 and 8 that was comparable with that seen in US-based participants in previous trials. Crisaborole had higher skin irritation than vehicle under occlusion in healthy Japanese adults and had an acceptable safety profile in Japanese adults with mild to moderate AD.

A Novel PET Probe for Brown Adipose Tissue Imaging in Rodents.

PURPOSE: Brown adipose tissue (BAT) has emerged as a promising target to counteract obesity and its associated metabolic disorders. However, the detection of this tissue remains one of the major roadblocks. PROCEDURES: In this study, we assess the use of BODIPY 1 as a positron emission tomography (PET) imaging agent to image BAT depots in vivo in two mouse phenotypes: obesity-resistant BALB/c mice and the obesity-prone C57BL/6 mice. [18F]BODIPY 1 is a radioactive dye that processed both radioactivity for PET imaging and fluorescence signal for in vitro mechanism study. RESULTS: Through the co-staining of cancer cells with BODIPY 1 and MitoTracker, we found BODIPY 1 mainly accumulated in cell mitochondria in vitro. Fluorescence imaging of primary brown and white adipocytes further confirmed BODIPY 1 had significantly higher accumulation in primary brown adipocytes compared with primary white adipocytes. We evaluated [18F]BODIPY 1 for BAT imaging in both obesity-resistant BALB/c mice and obesity-prone C57BL/6 mice. Indeed, [18F]BODIPY 1 was efficiently taken up by BAT in both mouse genotypes (6.40 ± 1.98 %ID/g in obesity-resistant BALB/c mice (n = 8) and 5.37 ± 0.82 %ID/g in obesity-prone C57BL/6 mice (n = 7)). Although norepinephrine stimulation could increase the absolute BAT uptake, the enhancement is not significant in both genotypes (p > 0.05) at current sample size. These results suggest BAT uptake of [18F]BODIPY 1 may be independent of BAT thermogenic activity. As a comparison, 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) PET imaging was performed in obesity-resistant BALB/c mice. Significantly increased uptake was observed in adrenergically activated BAT (10.08 ± 2.52 %ID/g, n = 3) but not in inactive BAT (3.803 ± 0.70 %ID/g; n = 3). Because [18F]BODIPY 1 maintained its fluorescent property, BAT tissue was excised and studied using fluorescence microscopy. Strong fluorescence signal was observed in BAT mouse that was injected with BODIPY 1. CONCLUSIONS: Unlike [18F]FDG, [18F]BODIPY 1 showed prominent accumulation in BAT under both inactive and stimulated status. [18F]BODIPY 1 may serve as a valuable BAT PET agent to possibly assess BAT mitochondria density, thus BAT thermogenic capacity after further evaluation.