Early Stage In Vitro Bioprofiling of Potential Low-Molecular-Weight Organoboron Compounds for Boron Neutron Capture Therapy (BNCT)-Proposal for a Guide.

Given the renewed interest in boron neutron capture therapy (BNCT) and the intensified search for improved boron carriers, as well as the difficulties of coherently comparing the carriers described so far, it seems necessary to define a basic set of assays and standardized methods to be used in the early stages of boron carrier development in vitro. The selection of assays and corresponding methods is based on the practical experience of the authors and is certainly not exhaustive, but open to discussion. The proposed tests/characteristics: Solubility, lipophilicity, stability, cytotoxicity, and cellular uptake apply to both low molecular weight (up to 500 Da) and high molecular weight (5000 Da and more) boron carriers. However, the specific methods have been selected primarily for low molecular weight boron carriers; in the case of high molecular weight compounds, some of the methods may need to be adapted.

Dumbbell-shaped bimetallic AuPd nanoenzymes for NIR-II cascade catalysis-photothermal synergistic therapy.

The noble metal NPs that are currently applied to photothermal therapy (PTT) have their photoexcitation location mainly in the NIR-I range, and the low tissue penetration limits their therapeutic effect. The complexity of the tumor microenvironment (TME) makes it difficult to inhibit tumor growth completely with a single therapy. Although TME has a high level of H2O2, the intratumor H2O2 content is still insufficient to catalyze the generation of sufficient hydroxide radicals (‧OH) to achieve satisfactory therapeutic effects. The AuPd-GOx-HA (APGH) was obtained from AuPd bimetallic nanodumbbells modified by glucose oxidase (GOx) and hyaluronic acid (HA) for photothermal enhancement of tumor starvation and cascade catalytic therapy in the NIR-II region. The CAT-like activity of AuPd alleviates tumor hypoxia by catalyzing the decomposition of H2O2 into O2. The GOx-mediated intratumoral glucose oxidation on the one hand can block the supply of energy and nutrients essential for tumor growth, leading to tumor starvation. On the other hand, the generated H2O2 can continuously supply local O2, which also exacerbates glucose depletion. The peroxidase-like activity of bimetallic AuPd can catalyze the production of toxic ‧OH radicals from H2O2, enabling cascade catalytic therapy. In addition, the high photothermal conversion efficiency (η = 50.7 %) of APGH nanosystems offers the possibility of photothermal imaging-guided photothermal therapy. The results of cell and animal experiments verified that APGH has good biosafety, tumor targeting, and anticancer effects, and is a precious metal nanotherapeutic system integrating glucose starvation therapy, nano enzyme cascade catalytic therapy, and PTT therapy. This study provides a strategy for photothermal-cascade catalytic synergistic therapy combining both exogenous and endogenous processes. STATEMENT OF SIGNIFICANCE: AuPd-GOx-HA cascade nanoenzymes were prepared as a potent cascade catalytic therapeutic agent, which enhanced glucose depletion, exacerbated tumor starvation and promoted cancer cell apoptosis by increasing ROS production through APGH-like POD activity. The designed system has promising photothermal conversion ability in the NIR-II region, simultaneously realizing photothermal-enhanced catalysis, PTT, and catalysis/PTT synergistic therapy both in vitro and in vivo. The present work provides an approach for designing and developing catalytic-photothermal therapies based on bimetallic nanoenzymatic cascades.

Next generation of boron neutron capture therapy (BNCT) agents for cancer treatment.

Boron neutron capture therapy (BNCT) is one of the most promising treatments among neutron capture therapies due to its long-term clinical application and unequivocally obtained success during clinical trials. Boron drug and neutron play an equivalent crucial role in BNCT. Nevertheless, current clinically used l-boronophenylalanine (BPA) and sodium borocaptate (BSH) suffer from large uptake dose and low blood to tumor selectivity, and that initiated overwhelm screening of next generation of BNCT agents. Various boron agents, such as small molecules and macro/nano-vehicles, have been explored with better success. In this featured article, different types of agents are rationally analyzed and compared, and the feasible targets are shared to present a perspective view for the future of BNCT in cancer treatment. This review aims at summarizing the current knowledge of a variety of boron compounds, reported recently, for the application of BCNT.

Nanostructured boron agents for boron neutron capture therapy: a review of recent patents.

Boron neutron capture therapy (BNCT) is a potential radiation therapy modality for cancer, and tumor-targeted stable boron-10 (10B) delivery agents are an important component of BNCT. Currently, two low-molecular-weight boron-containing compounds, sodium mercaptoundecahydro-closo-dodecaborate (BSH) and boronophenylalanine (BPA), are mainly used in BNCT. Although both have suboptimal tumor selectivity, they have shown some therapeutic benefit in patients with high-grade glioma and several other tumors. To improve the efficacy of BNCT, great efforts have been devoted for the development of new boron delivery agents with better uptake and favorable pharmacokinetic profiles. This article reviews the application and research progress of boron nanomaterials as boron carriers in boron neutron capture therapy and hopes to stimulate people's interest in nanomaterial-based delivery agents by summarizing various kinds of boron nanomaterial patents disclosed in the past decade.

Nanomaterial-assisted CRISPR gene-engineering - A hallmark for triple-negative breast cancer therapeutics advancement.

Triple-negative breast cancer (TNBC) is the most violent class of tumor and accounts for 20-24% of total breast carcinoma, in which frequently rare mutation occurs in high frequency. The poor prognosis, recurrence, and metastasis in the brain, heart, liver and lungs decline the lifespan of patients by about 21 months, emphasizing the need for advanced treatment. Recently, the adaptive immunity mechanism of archaea and bacteria, called clustered regularly interspaced short palindromic repeats (CRISPR) combined with nanotechnology, has been utilized as a potent gene manipulating tool with an extensive clinical application in cancer genomics due to its easeful usage and cost-effectiveness. However, CRISPR/Cas are arguably the efficient technology that can be made efficient via organic material-assisted approaches. Despite the efficacy of the CRISPR/Cas@nano complex, problems regarding successful delivery, biodegradability, and toxicity remain to render its medical implications. Therefore, this review is different in focus from past reviews by (i) detailing all possible genetic mechanisms of TNBC occurrence; (ii) available treatments and gene therapies for TNBC; (iii) overview of the delivery system and utilization of CRISPR-nano complex in TNBC, and (iv) recent advances and related toxicity of CRISPR-nano complex towards clinical trials for TNBC.

Using 157Gd doped carbon and 157GdF4 nanoparticles in proton-targeted therapy for effectiveness enhancement and thermal neutron reduction: a simulation study.

There are two major problems in proton therapy. (1) In comparison with the gamma-ray therapy, proton therapy has only ~ 10% greater biological effectiveness, and (2) the risk of the secondary neutrons in proton therapy is another unsolved problem. In this report, the increase of biological effectiveness in proton therapy has been evaluated with better performance than 11B in the presence of two proposed nanomaterials of 157GdF4 and 157Gd doped carbon with the thermal neutron reduction due to the presence of 157Gd isotope. The present study is based on the microanalysis calculations using GEANT4 Monte Carlo tool and GEANT4-DNA package for the strand breaks measurement. It was found that the proposed method will increase the effectiveness corresponding to the alpha particles by more than 100% and also, potentially will decrease the thermal neutrons fluence, significantly. Also, in this work, a discussion is presented on a significant contribution of the secondary alpha particles in total effectiveness in proton therapy.

The Role of Microbiome in Brain Development and Neurodegenerative Diseases.

Hundreds of billions of commensal microorganisms live in and on our bodies, most of which colonize the gut shortly after birth and stay there for the rest of our lives. In animal models, bidirectional communications between the central nervous system and gut microbiota (Gut-Brain Axis) have been extensively studied, and it is clear that changes in microbiota composition play a vital role in the pathogenesis of various neurodevelopmental and neurodegenerative disorders, such as Autism Spectrum Disorder, Alzheimer's disease, Parkinson's disease, Multiple Sclerosis, Amyotrophic Lateral Sclerosis, anxiety, stress, and so on. The makeup of the microbiome is impacted by a variety of factors, such as genetics, health status, method of delivery, environment, nutrition, and exercise, and the present understanding of the role of gut microbiota and its metabolites in the preservation of brain functioning and the development of the aforementioned neurological illnesses is summarized in this review article. Furthermore, we discuss current breakthroughs in the use of probiotics, prebiotics, and synbiotics to address neurological illnesses. Moreover, we also discussed the role of boron-based diet in memory, boron and microbiome relation, boron as anti-inflammatory agents, and boron in neurodegenerative diseases. In addition, in the coming years, boron reagents will play a significant role to improve dysbiosis and will open new areas for researchers.

Boron Chemicals in Drug Discovery and Development: Synthesis and Medicinal Perspective.

A standard goal of medicinal chemists has been to discover efficient and potent drug candidates with specific enzyme-inhibitor abilities. In this regard, boron-based bioactive compounds have provided amphiphilic properties to facilitate interaction with protein targets. Indeed, the spectrum of boron-based entities as drug candidates against many diseases has grown tremendously since the first clinically tested boron-based drug, Velcade. In this review, we collectively represent the current boron-containing drug candidates, boron-containing retinoids, benzoxaboroles, aminoboronic acid, carboranes, and BODIPY, for the treatment of different human diseases.In addition, we also describe the synthesis, key structure-activity relationship, and associated biological activities, such as antimicrobial, antituberculosis, antitumor, antiparasitic, antiprotozoal, anti-inflammatory, antifolate, antidepressant, antiallergic, anesthetic, and anti-Alzheimer's agents, as well as proteasome and lipogenic inhibitors. This compilation could be very useful in the exploration of novel boron-derived compounds against different diseases, with promising efficacy and lesser side effects.

Self-Assembled Monolayer of Monomercaptoundecahydro-closo-dodecaborate on a Polycrystalline Gold Surface.

In this work, we present an electrochemical study of the boron cage monomercaptoundecahydro-closo-dodecaborate [B12H11SH]2- in solution and in a self-assembled monolayer over a polycrystalline gold electrode. Cyclic voltammetry of the anion [B12H11SH]2- in solution showed a shift in the peak potentials related to the redox processes of gold hydroxides, which evidences the interaction between the boron cage and the gold surface. For an Au electrode modified with the anion [B12H11SH]2-, cyclic voltammetry response of the probe Fe(CN)63-/Fe(CN)64- showed a ΔEp value typical for a surface modification. Electrochemical impedance spectroscopy presented Rtc and Cdl values related to the formation of a self-assembled monolayer (SAM). A comparison of electrochemical responses of a modified electrode with thioglycolic acid (TGA) reveals that the boron cage [B12H11SH]2- diminishes the actives sites over the Au surface due to the steric effects. Differential capacitance measurements for bare gold electrode and those modified with [B12H11SH]2- and (TGA), indicate that bulky thiols enhance charge accumulation at the electrode-solution interface. In addition to electrochemical experiments, DFT calculations and surface plasmon resonance measurements (SPR) were carried out to obtain quantum chemical descriptors and to evaluate the molecular length and the dielectric constant of the Boron cage. From SPR experiments, the adsorption kinetics of [B12H11SH]2- were studied. The data fit for a Langmuir kinetic equation, typical for the formation of a monolayer.

Recent Advances in BODIPY Compounds: Synthetic Methods, Optical and Nonlinear Optical Properties, and Their Medical Applications.

Organoboron compounds are attracting immense research interest due to their wide range of applications. Particularly, low-coordinate organoboron complexes are receiving more attention due to their improbable optical and nonlinear optical properties, which makes them better candidates for medical applications. In this review, we summarize the various synthetic methods including multicomponent reactions, microwave-assisted and traditional pathways of organoboron complexes, and their optical and nonlinear properties. This review also includes the usage of organoboron complexes in various fields including biomedical applications.

Functionalized Boron Nanoparticles as Potential Promising Antimalarial Agents.

Boron nanoparticles (BNPs), functionalized with hydroxyl groups, were synthesized in situ by a cascade process, followed by bromination and hydrolyzation reactions. These functionalized BNPs, (B m (OH) n ), were characterized using 1H and 11B NMR spectra, Fourier-transform infrared (FT-IR) spectroscopy, inductively coupled plasma-optical emission spectroscopy (ICP-OES), transmission electron microscopy (TEM), dynamic light scattering (DLS), and X-ray photoelectron spectroscopy (XPS) methods. These nanoparticles were also evaluated in vitro for their antimalarial activity against Plasmodium falciparum (3D7 strain) with an IC50 value of 0.0021 µM and showed low toxicity to Uppsala 87 malignant glioma (U87MG) cell lines, malignant melanoma A375 cell lines, KB human oral cancer cell lines, rat cortical neuron cell lines, and rat fibroblast-like synoviocyte (FLS) cell lines.

Carboxyboranylamino ethanol: unprecedented discovery of boron agents for neutron capture therapy in cancer treatment.

Carboxyboranylamino ethanol (Me2N(BH2CO2H)CH2CH2OH, 1) was prepared in 75.0% yield by an amine-exchange reaction. Compound 1 shows lower cytotoxicity and higher anti-tumor efficacy in vitro towards the SCCVII cell line in comparison with 4-borono-L-phenylalanine (BPA) and methyl 2-hydroxyl-5-(1'-ortho-carbonylmethyl-1',2',3'-triazol-4'-yl)-benzonate (2). The bio-enhancement is interpreted using molecular docking calculations.

Organoboron Compounds: Effective Antibacterial and Antiparasitic Agents.

The unique electron deficiency and coordination property of boron led to a wide range of applications in chemistry, energy research, materials science and the life sciences. The use of boron-containing compounds as pharmaceutical agents has a long history, and recent developments have produced encouraging strides. Boron agents have been used for both radiotherapy and chemotherapy. In radiotherapy, boron neutron capture therapy (BNCT) has been investigated to treat various types of tumors, such as glioblastoma multiforme (GBM) of brain, head and neck tumors, etc. Boron agents playing essential roles in such treatments and other well-established areas have been discussed elsewhere. Organoboron compounds used to treat various diseases besides tumor treatments through BNCT technology have also marked an important milestone. Following the clinical introduction of bortezomib as an anti-cancer agent, benzoxaborole drugs, tavaborole and crisaborole, have been approved for clinical use in the treatments of onychomycosis and atopic dermatitis. Some heterocyclic organoboron compounds represent potentially promising candidates for anti-infective drugs. This review highlights the clinical applications and perspectives of organoboron compounds with the natural boron atoms in disease treatments without neutron irradiation. The main topic focuses on the therapeutic applications of organoboron compounds in the diseases of tuberculosis and antifungal activity, malaria, neglected tropical diseases and cryptosporidiosis and toxoplasmosis.

Effects of Linkers on the Development of Liposomal Formulation of Cholesterol Conjugated Cobalt Bis(dicarbollides).

Boron neutron capture therapy (BNCT) remains an important treatment arm for cancer patients with locally invasive malignant tumors. This therapy needs a significant amount of boron to deposit in cancer tissues selectively, sparing other healthy organs. Most of the liposomes contain water-soluble polyhedral boron salts stay in the core of the liposomes and have low encapsulation efficiency. Thus, modifying the polyhedral boron core to make it hydrophobic and incorporating those into the lipid layer could be one of the ways to increase drug loading and encapsulation efficiency. Additionally, a systematic study about the linker-dependent effect on drug encapsulation and drug-release is lacking, particularly for the liposomal formulation of hydrophobic-drugs. To achieve these goals, liposomal formulations of a series of lipid functionalized cobalt bis(dicarbollide) compounds have been prepared, with the linkers of different hydrophobicity. Hydrophobicity of the linkers have been evaluated through logP calculation and its effect on drug encapsulation and release have been investigated. The liposomes have shown high drug loading, excellent encapsulation efficiency, stability, and non-toxic behavior. Release experiment showed minimal release of drug from liposomes in phosphate buffer, ensuring some amount of drug, associated with liposomes, can be available to tumor tissues for Boron Neutron Capture Therapy.

Synthesis, Molecular Docking, and In Vitro Boron Neutron Capture Therapy Assay of Carboranyl Sinomenine.

In comparison with pristine sinomenine and carborane precursors, the calculations of molecular docking with matrix metalloproteinases (MMPs) and methylcarboranyl-n-butyl sinomenine showed improved interactions. Accordingly, methylcarboranyl-n-butyl sinomenine shows a high potential in the treatment of rheumatoid arthritis (RA) in the presence of slow neutrons. The reaction of potassium salt of sinomenie, which is generated from the deprotonation of sinomenine (1) using potassium carbonate in a solvent of N,N-dimethyl formamide, with 4-methylcarboranyl-n-butyl iodide, (2) forms methylcarboranyl-n-butyl sinomenine (3) in 54.3% yield as a new product. This new compound was characterized by 1H, 13C, and 11B NMR spectroscopy, FT-IR spectroscopy, and elemental analyses to confirm its molecular composition. In addition to molecular docking interactions with MMPs, the in vitro killing effects of 3, along with its toxicity measurements, exhibited its potential to be the new drug delivery agent for boron neutron capture synovectomy (BNCS) and boron neutron capture therapy (BNCT) for the treatment of rheumatoid arthritis (RA) and cancers in the presence of slow neutrons, respectively.

Carborane-Containing Matrix Metalloprotease (MMP) Ligands as Candidates for Boron Neutron-Capture Therapy (BNCT).

Based on the previously reported potent and selective sulfone hydroxamate inhibitors SC-76276, SC-78080 (SD-2590), and SC-77964, potent MMP inhibitors have been designed and synthesized to append a boron-rich carborane cluster by employing click chemistry to target tumor cells that are known to upregulate gelatinases. Docking against MMP-2 suggests binding involving the hydroxamate zinc-binding group, key H-bonds by the sulfone moiety with the peptide backbone residues Leu82 and Leu83, and a hydrophobic interaction with the deep P1' pocket. The more potent of the two triazole regioisomers exhibits an IC50 of 3.7 nM versus MMP-2 and IC50 of 46 nM versus MMP-9.

Boron-Containing Lipids and Liposomes: New Conjugates of Cholesterol with Polyhedral Boron Hydrides.

A series of boron-containing lipids were prepared by reactions of cyclic oxonium derivatives of polyhedron boranes and metallacarboranes (closo-dodecaborate anion, cobalt and iron bis(dicarbollides)) with amine and carboxylic acids which are derived from cholesterol. Stable liposomal formulations, on the basis of synthesized boron-containing lipids, hydrogenated soybean l-α-phosphatidylcholine and (HSPC) 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (DSPE-PEG) as excipients, were prepared and then characterized by dynamic light scattering (DLS) that revealed the formation of particles to be smaller than 200 nm in diameter. The resulting liposomal formulations showed moderate to excellent loading and entrapment efficiency, thus justifying the design of the compounds to fit in the lipid bilayer and ensuring ease of in vivo use for future application. The liposomal formulations based on cobalt and iron bis(dicarbollide)-based lipids were found to be nontoxic against both human breast normal epithelial cells MCF-10A and human breast cancer cells MCF-7.

Enhancement of Radiation Effectiveness in Proton Therapy: Comparison Between Fusion and Fission Methods and Further Approaches.

Proton therapy as a promising candidate in cancer treatment has attracted much attentions and many studies have been performed to investigate the new methods to enhance its radiation effectiveness. In this regard, two research groups have suggested that using boron isotopes will lead to a radiation effectiveness enhancement, using boron-11 agent to initiate the proton fusion reaction (P-BFT) and using boron-10 agent to capture the low energy secondary neutrons (NCEPT). Since, these two innovative methods have not been approved clinically, they have been recalculated in this report, discussed and compared between them and also with the traditional proton therapy to evaluate their impacts before the experimental investigations. The calculations in the present study were performed by Geant4 and MCNPX Monte Carlo Simulation Codes were utilized for obtaining more precision in our evaluations of these methods impacts. Despite small deviations in the results from the two MC tools for the NCEPT method, a good agreement was observed regarding the delivered dose rate to the tumor site at different depths while, for P-BFT related calculations, the GEANT4 was in agreement with the analytical calculations by means of the detailed cross-sections of proton-11B fusion. Accordingly, both the methods generate excess dose rate to the tumor several orders of magnitude lower than the proton dose rate. Also, it was found that, the P-BFT has more significant enhancement of effectiveness, when compared to the NCEPT, a method with impact strongly depended on the tumor's depth. On the other hand, the advantage of neutron risk reduction proposed by NCEPT was found to give no considerable changes in the neutron dose absorption by healthy tissues.

The Transition from Metal-Based to Metal-Free Contrast Agents for T1 Magnetic Resonance Imaging Enhancement.

Magnetic resonance imaging (MRI) has received significant attention as the noninvasive diagnostic technique for complex diseases. Image-guided therapeutic strategy for diseases such as cancer has also been at the front line of biomedical research, thanks to the innovative MRI, enhanced by the prior delivery of contrast agents (CAs) into patients' bodies through injection. These CAs have contributed a great deal to the clinical utility of MRI but have been based on metal-containing compounds such as gadolinium, manganese, and iron oxide. Some of these CAs have led to cytotoxicities such as the incurable Nephrogenic Systemic Fibrosis (NSF), resulting in their removal from the market. On the other hand, CAs based on organic nitroxide radicals, by virtue of their structural composition, are metal free and without the aforementioned drawbacks. They also have improved biocompatibility, ease of functionalization, and long blood circulation times, and have been proven to offer tissue contrast enhancement with longitudinal relaxivities comparable with those for the metal-containing CAs. Thus, this Review highlights the recent progress in metal-based CAs and their shortcomings. In addition, the remarkable goals achieved by the organic nitroxide radical CAs in the enhancement of MR images have also been discussed extensively. The focal point of this Review is to emphasize or demonstrate the crucial need for transition into the use of organic nitroxide radicals-metal-free CAs-as against the metal-containing CAs, with the aim of achieving safer application of MRI for early disease diagnosis and image-guided therapy.

Synthesis and in vitro anti-tumor activity of carboranyl levodopa.

Reactions of closo-1-Me-2-Iodobutyl-1,2-closo-dicarborane, 1-Me-2-I(CH2)4-C2B10H10, with l-dopa methyl ester can produce carboranyl l-dopa methyl esters in 54% yield in the presence of sodium hydroxide. The appended closo-carboranes can be decapitated with sodium hydroxide in a mixed solvent of ethanol and deionized water to produce highly water-soluble carboranyl levodopa in 64% yield. All the new compounds were characterized by 1H, 13C, 11B NMR, FT-IR spectroscopy and elemental analysis. The highly water soluble carboranyl levodopa 4 shows promising efficacy of anti-tumors in vitro in the presence of slow neutron beams.