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.

[Clinical Efficacy and Safety of Ixazomib-Containing Regimens in the Treatment of Patients with Multiple Myeloma].

OBJECTIVE: To investigate the clinical efficacy and safety of ixazomib-containing regimens in the treatment of patients with multiple myeloma (MM). METHODS: A retrospective analysis was performed on the clinical efficacy and adverse reactions of 32 MM patients treated with a combined regimen containing ixazomib in the Hematology Department of the First People's Hospital of Lianyungang from January 2020 to February 2022. Among the 32 patients, 15 patients were relapsed and refractory multiple myeloma (R/RMM) (R/RMM group), 17 patients who responded to bortezomib induction therapy but converted to ixazomib-containing regimen due to adverse events (AE) or other reasons (conversion treatment group). The treatment included IPD regimen (ixazomib+pomalidomide+dexamethasone), IRD regimen (ixazomib+lenalidomide+dexamethasone), ICD regimen (ixazomib+cyclophosphamide+dexamethasone), ID regimen (ixazomib+dexamethasone). RESULTS: Of 15 R/RMM patients, overall response rate (ORR) was 53.3%(8/15), among them, 1 achieved complete response (CR), 2 achieved very good partial response (VGPR) and 5 achieved partial response (PR). The ORR of the IPD, IRD, ICD and ID regimen group were 100%（3/3）, 42.9%（3/7）, 33.3%（1/3）, 50%（1/2）， respectively， there was no statistically significant difference in ORR between four groups (χ 2=3.375, P =0.452). The ORR of patients was 50% after first-line therapy, 42.9% after second line therapy, 60% after third line therapy or more, with no statistically significant difference among them (χ2=2.164, P =0.730). In conversion treatment group, ORR was 88.2%(15/17), among them, 6 patients achieved CR, 5 patients achieved VGPR and 4 patients achieved PR. There was no statistically significant difference in ORR between the IPD（100%， 3/3）, IRD（100%， 6/6）, ICD（100%， 3/3） and ID（60%， 3/5） regimen groups (χ2=3.737，P =0.184). The median progression-free survival (PFS) time of R/RMM patients was 9 months (95% CI : 6.6-11.4 months), the median overall survival (OS) time was 18 months (95% CI : 11.8-24.4 months). The median PFS time of conversion treatment group was 15 months (95% CI : 7.3-22.7 months), the median OS time not reached. A total of 10 patients suffered grade 3- 4 adverse event (AE). The common hematological toxicities were leukocytopenia, anemia, thrombocytopenia. The common non-hematological toxicities were gastrointestinal symptoms (diarrhea, nausea and vomit), peripheral neuropathy, fatigue and infections. Grade 1-2 peripheral neurotoxicity occurred in 7 patients. CONCLUSION: The ixazomib-based chemotherapy regimens are safe and effective in R/RMM therapy, particularly for conversion patients who are effective for bortezomib therapy. The AE was manageable and safe.

Assessment of prolonged proteasome inhibition through ixazomib-based oral regimen on newly diagnosed and first-relapsed multiple myeloma: A real-world Chinese cohort study.

OBJECTIVE: To evaluate the effectiveness, safety, and convenience of in-class transition (iCT) from intravenous bortezomib-based induction to ixazomib-based oral regimens. METHODS: This retrospective real-world study was conducted in 16 Chinese hospitals between October 2017 and April 2023 and analyzed newly diagnosed (NDMM) and first-line relapsed multiple myeloma (FRMM) patients who attained at least a partial response from bortezomib-based induction therapy, followed by an ixazomib-based oral regimen for 2 year or until disease progression or intolerable toxicity. RESULTS: The study enrolled 199 patients, median age: 63 years old, male 55.4%, 53% as high risk (HR), and 47% as standard risk. Cytogenetic risk stratification by metaphase fluorescence in situ hybridization (M-FISH), based on the Mayo Clinic risk stratification system. The median duration of total PI therapy was 11 months, with ixazomib-based treatment spanning 6 months. At the 20-month median follow-up, 53% of patients remained on therapy. The 24-month PFS rate was 84.3% from the initiation of bortezomib-based induction and 83.4% from the start of ixazomib-based treatment. Overall response rate (ORR) was 100% post-bortezomib induction and 90% following 6 cycles of the ixazomib-based regimen. Based on the Sankey diagrams, 89.51% of patients maintained or improved their disease response after 2 cycles of iCT, 6 cycles (90.14%), and 12 cycles (80%). The HR level of Mayo was found to be a significant independent factor in a worse remission (hazard ratio (HR) 2.55; p = 0.033). Ixazomib's safety profile aligned with previous clinical trial data, with 49% of patients experiencing at least one AE of any grade. The most common AEs included peripheral neuropathy, nausea and vomiting, diarrhea, thrombocytopenia, and granulocytopenia. CONCLUSION: In the real-world Chinese MM population, NDMM and FRMM patients responded favorably to PI-based continuous therapy, demonstrating substantial response rates. The ixazomib-based iCT allows for sustained PI-based treatment, offering promising efficacy and tolerable AEs.

Combining BNCT with carbonic anhydrase inhibition for mesothelioma treatment: Synthesis, in vitro, in vivo studies of ureidosulfamido carboranes.

Mesothelioma is a malignant neoplasm of mesothelial cells caused by exposure to asbestos. The average survival time after diagnosis is usually nine/twelve months. A multi-therapeutic approach is therefore required to treat and prevent recurrence. Boronated derivatives containing a carborane cage, a sulfamido group and an ureido functionality (CA-USF) have been designed, synthesised and tested, in order to couple Boron Neutron Capture Therapy (BNCT) and the inhibition of Carbonic Anhydrases (CAs), which are overexpressed in many tumours. In vitro studies showed greater inhibition than the reference drug acetazolamide (AZ). To increase solubility in aqueous media, CA-USFs were used as inclusion complexes of hydroxypropyl ß-cyclodextrin (HP-ß-CD) in all the inhibition and cell experiments. BNCT experiments carried out on AB22 (murine mesothelioma) cell lines showed a marked inhibition of cell proliferation by CA-USFs, and in one case a complete inhibition of proliferation twenty days after neutron irradiation. Finally, in vivo neutron irradiation experiments on a mouse model of mesothelioma demonstrated the efficiency of combining CA IX inhibition and BNCT treatment. Indeed, a greater reduction in tumour mass was observed in treated mice compared to untreated mice, with a significant higher effect when combined with BNCT. For in vivo experiments CA-USFs were administered as inclusion complexes of higher molecular weight ß-CD polymers thus increasing the selective extravasation into tumour tissue and reducing clearance. In this way, boron uptake was maximised and CA-USFs demonstrated to be in vivo well tolerated at a therapeutic dose. The therapeutic strategy herein described could be expanded to other cancers with increased CA IX activity, such as melanoma, glioma, and breast cancer.

INSURE: a pooled analysis of ixazomib-lenalidomide-dexamethasone for relapsed/refractory myeloma in routine practice.

Aim: We pooled data from three observational studies (INSIGHT MM, UVEA-IXA and REMIX) to investigate the real-world effectiveness of ixazomib-lenalidomide-dexamethasone (IRd) in relapsed/refractory myeloma. Materials & methods: INSIGHT MM was a prospective study conducted in countries across Europe, Asia and North/Latin America while UVEA-IXA and REMIX were multicenter, retrospective/prospective studies conducted in Europe. Patients who had received IRd as ≥2nd line of therapy were analyzed. Primary outcomes were time-to-next treatment (TTNT) and progression-free survival (PFS). Results: Overall, 564 patients were included (median follow-up: 18.5 months). Median TTNT and PFS were 18.4 and 19.9 months; both outcomes were numerically longer for earlier versus later lines. Median treatment duration was 14.0 months. Overall response rate was 64.6%. No new safety concerns were noted. Conclusion: The effectiveness of IRd in routine practice appears similar to the efficacy observed in TOURMALINE-MM1. IRd benefit in earlier versus later lines was consistent with previous reports.

A phase II study of ibrutinib in combination with ixazomib in patients with Waldenström macroglobulinaemia.

This phase II study evaluated time-limited (24 cycles) treatment with ibrutinib and ixazomib in newly diagnosed (NDWM; n = 9) and relapsed/refractory (RRWM; n = 12) Waldenström macroglobulinaemia (WM). The overall response rate (ORR) was 76.2% (n = 16) in 21 evaluable patients with no patient achieving a complete response (CR). The median duration of treatment was 15.6 months, and after a median follow-up time of 25.7 months, the median progression-free survival (PFS) was 22.9 months. While the primary end-point was not met (CR rate at any time) and 28.5% discontinued treatment due to toxicity, ibrutinib plus ixazomib led to a clinically meaningful ORR and PFS. Combined Bruton's tyrosine kinase (BTK) and proteasome inhibition merits further evaluation in WM.

Tuning Shortwave-Infrared J-aggregates of Aromatic Ring-Fused Aza-BODIPYs by Peripheral Substituents for Combined Photothermal and Photodynamic Therapies at Ultralow Laser Power.

Achieving photothermal therapy (PTT) at ultralow laser power density is crucial for minimizing photo-damage and allowing for higher maximum permissible skin exposure. However, this requires photothermal agents to possess not just superior photothermal conversion efficiency (PCE), but also exceptional near-infrared (NIR) absorptivity. J-aggregates, exhibit a significant redshift and narrower absorption peak with a higher extinction coefficient. Nevertheless, achieving predictable J-aggregates through molecular design remains a challenge. In this study, we successfully induced desirable J-aggregation (λabs max : 968 nm, ϵ: 2.96×105  M-1 cm-1 , λem max : 972 nm, ΦFL : 6.2 %) by tuning electrostatic interactions between π-conjugated molecular planes through manipulating molecular surface electrostatic potential of aromatic ring-fused aza-BODIPY dyes. Notably, by controlling the preparation method for encapsulating dyes into F-127 polymer, we were able to selectively generate H-/J-aggregates, respectively. Furthermore, the J-aggregates exhibited two controllable morphologies: nanospheres and nanowires. Importantly, the shortwave-infrared J-aggregated nanoparticles with impressive PCE of 72.9 % effectively destroyed cancer cells and mice-tumors at an ultralow power density of 0.27 W cm-2 (915 nm). This phototherapeutic nano-platform, which generates predictable J-aggregation behavior, and can controllably form J-/H-aggregates and selectable J-aggregate morphology, is a valuable paradigm for developing photothermal agents for tumor-treatment at ultralow laser power density.

Lysosome-targeted Aza-BODIPY photosensitizers for anti-cancer photodynamic therapy.

Developing effective near-infrared (NIR) photosensitizers (PSs) has been an attractive goal of photodynamic therapy (PDT) for cancer treatment. In this study, we synthesized N, N-diethylaminomethylphenyl-containing Aza-BODIPY photosensitizers and comprehensively investigated their photophysical/photochemical properties, as well as cell-based and animal-based anti-tumor studies. Among them, BDP 1 has strong NIR absorption at 680 nm and higher singlet oxygen yield in PBS which showed favorable pH-activatable and lysosome-targeting ability. BDP 1 could be easily taken up by tumor cells and showed negligible dark activity (IC50 > 50 µM), however strong phototoxicity upon exposure to light irradiation. The acceptable fluorescence emission from BDP 1 allowed convenient in vivo fluorescence imaging for organ distribution studies in mice. After PDT treatment with upon single time PDT treatment at the beginning using relatively low light dose (54 J/ cm2), BDP 1 (2 mg/kg, 0.1 mL) was found to have strong efficacy to inhibit tumor growth and even to ablate off tumor without causing body weight loss. Therefore, pH-activatable and lysosome-targeted PS may become an effective way to develop potent PDT agent.

Impact of Crisaborole in Treatment-Experienced Patients With Mild-to-Moderate Atopic Dermatitis.

Background: Crisaborole ointment, 2%, is a nonsteroidal phosphodiesterase 4 inhibitor for the treatment of patients with mild-to-moderate atopic dermatitis (AD). Objective: To assess the efficacy and safety of crisaborole in patients with AD who had received prior treatment with (a) corticosteroids (systemic or topical) or topical calcineurin inhibitors (TCIs) or (b) topical corticosteroids (TCSs) or TCIs or (c) who were treatment-naive (TN). Methods: This post hoc analysis comprised patients aged ≥2 years with mild-to-moderate AD. Patients were assigned (2:1) to receive crisaborole or vehicle twice daily for 28 days. Patient response was assessed with the Investigator's Static Global Assessment (ISGA), Dermatology Life Quality Index (DLQI), Children's Dermatology Life Quality Index (CDLQI), and Dermatitis Family Impact (DFI) tools. Safety was also assessed. Results: A significantly higher percentage of patients treated with crisaborole versus vehicle achieved ISGA success regardless of treatment history. Patients treated with crisaborole had significant reductions in DLQI, CDLQI, and DFI scores versus those who received vehicle regardless of treatment history, with the exception of DLQI and DFI scores in the TN group. Crisaborole was well tolerated in all subgroups. Conclusion: Crisaborole demonstrated a favorable efficacy and safety profile in both treatment-experienced and TN patients. ClinicalTrials.gov, NCT02118766 and NCT02118792.

Revolutionary Pyrazole-based Aza-BODIPY: Harnessing Photothermal Power Against Cancer Cells and Bacteria.

In the realm of cancer therapy and treatment of bacterial infection, photothermal therapy (PTT) stands out as a potential strategy. The challenge, however, is to create photothermal agents that can perform both imaging and PTT, a so-called theranostic agent. Photothermal agents that absorb and emit in the near-infrared region (750-900 nm) have recently received a lot of attention due to the extensive penetration of NIR light in biological tissues. In this study, we combined pyrazole with aza-BODIPY (PY-AZB) to develop a novel photothermal agent. PY-AZB demonstrated great photostability with a photothermal conversion efficiency (PCE) of up to 33 %. Additionally, PY-AZB can permeate cancer cells at a fast accumulation rate in less than 6 hours, according to the confocal images. Furthermore, in vitro photothermal therapy results showed that PY-AZB effectively eliminated cancer cells by up to 70 %. Interestingly, PY-AZB exhibited antibacterial activities against both gram-negative bacteria, Escherichia coli 780, and gram-positive bacteria, Staphylococcus aureus 1466. The results exhibit a satisfactory bactericidal effect against bacteria, with a killing efficiency of up to 100 % upon laser irradiation. As a result, PY-AZB may provide a viable option for photothermal treatment.

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.

BODIPY-Based Molecules for Biomedical Applications.

BODIPY (4,4-difluoro-4-bora-3a,4a-diaza-s-indacene) derivatives have attracted attention as probes in applications like imaging and sensing due to their unique properties like (1) strong absorption and emission in the visible and near-infrared regions of the electromagnetic spectrum, (2) strong fluorescence and (3) supreme photostability. They have also been employed in areas like photodynamic therapy. Over the last decade, BODIPY-based molecules have even emerged as candidates for cancer treatments. Cancer remains a significant health issue world-wide, necessitating a continuing search for novel therapeutic options. BODIPY is a flexible fluorophore with distinct photophysical characteristics and is a fascinating drug development platform. This review provides a comprehensive overview of the most recent breakthroughs in BODIPY-based small molecules for cancer or disease detection and therapy, including their functional potential.

Boron in cancer therapeutics: An overview.

Boron has become a crucial weapon in anticancer research due to its significant intervention in cell proliferation. Being an excellent bio-isosteric replacement of carbon, it has modulated the anticancer efficacy of various molecules in the development pipeline. It has elicited promising results through interactions with various therapeutic targets such as HIF-1α, steroid sulfatase, arginase, proteasome, etc. Since boron liberates alpha particles, it has a wide-scale application in Boron Neutron Capture therapy (BNCT), a radiotherapy that demonstrates selectivity towards cancer cells due to high boron uptake capacity. Significant advances in the medicinal chemistry of boronated compounds, such as boronated sugars, natural/unnatural amino acids, boronated DNA binders, etc., have been reported over the past few years as BNCT agents. In addition, boronated nanoparticles have assisted the field of bio-nano medicines by their usage in radiotherapy. This review exclusively focuses on the medicinal chemistry aspects, radiotherapeutic, and chemotherapeutic aspects of boron in cancer therapeutics. Emphasis is also given on the mechanism of action along with advantages over conventional therapies.

Correlation between L-amino acid transporter 1 expression and 4-borono-2-18 F-fluoro-phenylalanine accumulation in humans.

BACKGROUND: The correlation between L-type amino acid transporter 1 (LAT1) expression and 4-borono-2-18 F-fluoro-phenylalanine (18 F-FBPA) accumulation in humans remains unclear. This study aimed to investigate the correlation between LAT1 expression in tumor tissues and 18 F-FBPA accumulation in patients with head and neck cancer who participated in a clinical trial of 18 F-FBPA positron emission tomography (PET). METHODS: Altogether, 28 patients with head and neck cancer who participated in a clinical trial of 18 F-FBPA PET at our institution between March 2012 and January 2018 were included. Correlations between standardized uptake values (SUVs); the maximum SUV (SUVmax ), the mean SUV within a 1 cm3 sphere centered at a single point, that is, the SUVmax (SUVpeak ), the minimum SUV (SUVmin ), and the intensity of LAT1 expression (maximum and minimum LAT1 expressions) were investigated. RESULTS: Weak correlations were identified between SUVmax and LAT1 maximum score, SUVmin and LAT1 maximum score, and SUVmin and LAT1 minimum score (ρ = 0.427, 0.362, and 0.330, respectively). SUVmax and LAT1 minimum score, SUVpeak and LAT1 maximum score, and SUVpeak and LAT1 minimum score demonstrated moderate correlations (ρ = 0.535, 0.556, and 0.661, respectively). Boron neutron capture therapy (BNCT) was performed in 2 of the 4 patients with discrepancies between 18 F-FBPA accumulation and intensity of LAT1 expression, and the intensity of LAT1 expression was a better predictor of treatment response. CONCLUSION: 18 F-FBPA accumulation and the intensity of LAT1 expression demonstrated a moderate correlation; however, LAT1 expression may be a better predictor of treatment response of BNCT in patients with discrepancies.

Proposal of recommended experimental protocols for in vitro and in vivo evaluation methods of boron agents for neutron capture therapy.

Recently, boron neutron capture therapy (BNCT) has been attracting attention as a minimally invasive cancer treatment. In 2020, the accelerator-based BNCT with L-BPA (Borofalan) as its D-sorbitol complex (Steboronine®) for head and neck cancers was approved by Pharmaceutical and Medical Devices Agency for the first time in the world. As accelerator-based neutron generation techniques are being developed in various countries, the development of novel tumor-selective boron agents is becoming increasingly important and desired. The Japanese Society of Neutron Capture Therapy believes it is necessary to propose standard evaluation protocols at each stage in the development of boron agents for BNCT. This review summarizes recommended experimental protocols for in vitro and in vivo evaluation methods of boron agents for BNCT based on our experience with L-BPA approval.

Next-Generation Boron Drugs and Rational Translational Studies Driving the Revival of BNCT.

BNCT is a high-linear-energy transfer therapy that facilitates tumor-directed radiation delivery while largely sparing adjacent normal tissues through the biological targeting of boron compounds to tumor cells. Tumor-specific accumulation of boron with limited accretion in normal cells is the crux of successful BNCT delivery. Given this, developing novel boronated compounds with high selectivity, ease of delivery, and large boron payloads remains an area of active investigation. Furthermore, there is growing interest in exploring the immunogenic potential of BNCT. In this review, we discuss the basic radiobiological and physical aspects of BNCT, traditional and next-generation boron compounds, as well as translational studies exploring the clinical applicability of BNCT. Additionally, we delve into the immunomodulatory potential of BNCT in the era of novel boron agents and examine innovative avenues for exploiting the immunogenicity of BNCT to improve outcomes in difficult-to-treat malignancies.

The effects of BPA-BNCT on normal bone: determination of the CBE value in mice‡.

Boron neutron capture therapy (BNCT) with p-boronophenylalanine (BPA) is expected to have less effect on the decrease in normal bone strength than X-ray therapy. However, the compound biological effectiveness (CBE) value necessary to convert the boron neutron capture reaction (BNCR) dose into a bioequivalent X-ray dose has not been determined yet. The purpose of this study was to evaluate the influence of BNCT on normal bone in mice and to elucidate the CBE factor. We first searched the distribution of BPA in the normal bone of C3H/He mice and then measured the changes in bone strength after irradiation. The CBE value was determined when the decrease in bone strength was set as an index of the BNCT effect. The 10B concentrations in the tibia after subcutaneous injection of 125, 250 and 500 mg/kg BPA were measured by prompt gamma-ray spectroscopy and inductively coupled plasma (ICP)-atomic emission spectrometry. The 10B mapping in the tibia was examined by alpha-track autoradiography and laser ablation-ICP-mass spectrometry. The 10B concentration increased dose-dependently; moreover, the concentrations were maintained until 120 min after BPA administration. The administered 10B in the tibia was abundantly accumulated in the growth cartilage, trabecular bone and bone marrow. The bone strength was analyzed by a three-point bending test 12 weeks after irradiation. The bending strength of the tibia decreased dose-dependently after the irradiation of X-ray, neutron and BNCR. The CBE factor was obtained as 2.27 by comparing these dose-effect curves; the value determined in this study will enable an accurate dosimetry of normal bone.

Diastereoselective Synthesis of the Borylated d-Galactose Monosaccharide 3-Boronic-3-Deoxy-d-Galactose and Biological Evaluation in Glycosidase Inhibition and in Cancer for Boron Neutron Capture Therapy (BNCT).

Drug leads with a high Fsp3 index are more likely to possess desirable properties for progression in the drug development pipeline. This paper describes the development of an efficient two-step protocol to completely diastereoselectively access a diethanolamine (DEA) boronate ester derivative of monosaccharide d-galactose from the starting material 1,2:5,6-di-O-isopropylidene-α-d-glucofuranose. This intermediate, in turn, is used to access 3-boronic-3deoxy-d-galactose for boron neutron capture therapy (BNCT) applications. The hydroboration/borane trapping protocol was robustly optimized with BH3.THF in 1,4-dioxane, followed by in-situ conversion of the inorganic borane intermediate to the organic boron product by the addition of DEA. This second step occurs instantaneously, with the immediate formation of a white precipitate. This protocol allows expedited and greener access to a new class of BNCT agents with an Fsp3 index = 1 and a desirable toxicity profile. Furthermore, presented is the first detailed NMR analysis of the borylated free monosaccharide target compound during the processes of mutarotation and borarotation.

Evaluating the biological effectiveness of boron neutron capture therapy by using microfluidics-based pancreatic tumor spheroids.

Background: The recent success of boron neutron capture therapy (BNCT) for cancer treatment has attracted considerable attention. Because irradiated neutrons penetrate deep into solid tumor tissue, BNCT efficacy is strongly influenced by cell pathophysiology in tumors. The tumor microenvironment critically influences tumor pathophysiology, but its effects on BNCT remain unexplored. Methods: We used a pancreatic tumor as a model to develop a high-throughput 3D tumor spheroid platform for evaluating BNCT efficacy under different microenvironment conditions. We expanded our system to serve as a transwell-like device in order to investigate the influence of stromal fibroblasts in the tumor microenvironment. Results: With the use of the proposed microfluidic chip and a laboratory pipette, more than 40 spheroids with controllable diameters (standard deviation <10%) could be cultured on a chip for more than 10 days. The response to BNCT from each spheroid can be monitored in real time. By using pancreatic tumor spheroids of two different diameters, we found that large spheroids, characterized by more hypoxic microenvironments, exhibited lower BNCT susceptibility. The cells in the hypoxic region expressed the HIF1-α signal, which is crucial in many therapeutic resistance signal pathways. In addition, the heterogeneous presence of stemness markers (Oct-4, Sox-2, and CD 44) implied that the underlying BNCT resistance mechanism was sophisticated. In the presence of fibroblasts, we found an association between ß-catenin nuclear translocation and BNCT resistance; membrane contacts from fibroblasts were found to be indispensable for translocation activation. Conclusions: In summary, by means of easily accessible microfluidic engineering, we developed tumor spheroids to recapture the pathophysiological characteristics of pancreatic tumors. Our data suggest that hypoxia and fibrosis can reduce BNCT efficacy in pancreatic cancer treatment. Considering the growing requirement for drug screening in personalized medicine, our findings and the developed method are expected to improve the fundamental understanding of BNCT and facilitate broad applications of BNCT in clinical settings.