Combined Gadolinium and Boron Neutron Capture Therapies for Eradication of Head-and-Neck Tumor Using Gd10B6 Nanoparticles under MRI/CT Image Guidance
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SUBMITTER: Shanmugam M
PROVIDER: S-EPMC10466345 | biostudies-literature | 2023 Aug
REPOSITORIES: biostudies-literature
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Project description:PurposeGadolinium-neutron capture therapy (Gd-NCT) employs isotopically enriched Gadolinium (Gd) and thermal neutrons to selectively target cancer cells. This study investigated the targeting efficacy of 157Gd-DOTA-PSMA (Prostate-Specific Membrane Antigen) in prostate cancer and explored its potential applications in Gd-NCT.Methods and resultsWe developed 157Gd-DOTA-PSMA, a novel theranostic bio-gadolinium agent specifically designed for magnetic resonance imaging (MRI)-guided Gd-NCT. 68 Ga-DOTA-PSMA positron emission tomography-computed tomography (PET/CT) imaging showed peak radiotracer uptake at 2 h post-injection, with a tumor-to-non-tumor (T/NT) ratio of 6.95 ± 0.60. MRI analysis confirmed a stable T1 signal enhancement 2 h post-injection. Time-of-flight inductively coupled plasma mass spectrometry (TOF-ICP-MS) revealed significantly elevated Gd concentrations in 22Rv1 tumor compared to PC-3 tumor and other healthy organs. ICP-MS analysis showed Gd concentrations of 165.69 μg [Gd]/g in 22Rv1 tumors and 35.25 μg [Gd]/g in blood, yielding a tumor-to-blood (T/B) ratio of 4.65 ± 0.54 and a T/NT ratio of 3.65 ± 0.49. Neutron irradiation with 157Gd-DOTA-PSMA reduced cell viability, inhibited colony formation, and induced DNA damage and apoptosis in 22Rv1 cells. In 22Rv1 mice, γ-H2AX levels peaked at 6 h post-irradiation, accompanied by an increase in pro-apoptotic proteins and a decrease in anti-apoptotic proteins over 24 h. In the NCT group following the injection of 157Gd-DOTA-PSMA, there was effective suppression of tumor growth without a loss of body weight, resulting in a 1.7-fold increase in median survival compared to control group.Conclusions157Gd-DOTA-PSMA, as a theranostic bio-gadolinium agent designed for targeted Gd-NCT in prostate cancer, represents a novel therapeutic approach and broadens the scope of potential applications of neutron capture therapy.
| S-EPMC11861226 | biostudies-literature
Project description:In this article, a novel method of simultaneous carborane- and gadolinium-containing compounds as efficient agents for neutron capture therapy (NCT) delivery via magnetic nanocarriers is presented. The presence of both Gd and B increases the efficiency of NCT and using nanocarriers enhances selectivity. These factors make NCT not only efficient, but also safe. Superparamagnetic Fe3O4 nanoparticles were treated with silane and then the polyelectrolytic layer was formed for further immobilization of NCT agents. Fourier-transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), energy dispersive X-ray (EDX), ultraviolet-visible (UV-Vis) and Mössbauer spectroscopies, dynamic light scattering (DLS), scanning electron microscopy (SEM), vibrating-sample magnetometry (VSM) were applied for the characterization of the chemical and element composition, structure, morphology and magnetic properties of nanocarriers. The cytotoxicity effect was evaluated on different cell lines: BxPC-3, PC-3 MCF-7, HepG2 and L929, human skin fibroblasts as normal cells. average size of nanoparticles is 110 nm; magnetization at 1T and coercivity is 43.1 emu/g and 8.1, respectively; the amount of B is 0.077 mg/g and the amount of Gd is 0.632 mg/g. Successful immobilization of NCT agents, their low cytotoxicity against normal cells and selective cytotoxicity against cancer cells as well as the superparamagnetic properties of nanocarriers were confirmed by analyses above.
| S-EPMC8395504 | biostudies-literature
Project description:Knowledge of the 10B microdistribution is of great relevance in BNCT studies. Since 10B concentration assesment through neutron autoradiography depends on the correct quantification of tracks in a nuclear track detector, image acquisition and processing conditions should be controlled and verified, in order to obtain accurate results to be applied in the frame of BNCT. With this aim, an image verification process was proposed, based on parameters extracted from the quantified nuclear tracks. Track characterization was performed by selecting a set of morphological and pixel-intensity uniformity parameters from the quantified objects (area, diameter, roundness, aspect ratio, heterogeneity and clumpiness). Their distributions were studied, leading to the observation of varying behaviours in images generated by different samples and acquisition conditions. The distributions corresponding to samples coming from the BNC reaction showed similar attributes in each analyzed parameter, proving to be robust to the experimental process, but sensitive to light and focus conditions. Considering those observations, a manual feature extraction was performed as a pre-processing step. A Support Vector Machine (SVM) and a fully dense Neural Network (NN) were optimized, trained, and tested. The final performance metrics were similar for both models: 93%-93% for the SVM, vs 94%-95% for the NN in accuracy and precision respectively. Based on the distribution of the predicted class probabilities, the latter had a better capacity to reject inadequate images, so the NN was selected to perform the image verification step prior to quantification. The trained NN was able to correctly classify the images regardless of their track density. The exhaustive characterization of the nuclear tracks provided new knowledge related to the autoradiographic images generation. The inclusion of machine learning in the analysis workflow proves to optimize the boron determination process and paves the way for further applications in the field of boron imaging.
| S-EPMC10735019 | biostudies-literature
Project description:Interest in the design of boronated amino acids has emerged, partly due to the utilization of boronophenylalanine (BPA), one of the two agents employed in clinical Boron Neutron Capture Therapy (BNCT). The boronated amino acids synthesized thus far for BNCT investigations can be classified into two categories based on the source of boron: boronic acids or carboranes. Amino acid-based boron carriers, employed in the context of BNCT treatment, demonstrate significant potential in the treatment of challenging tumors, such as those located in the brain. This review aims to shed light on the developmental journey and challenges encountered over the years in the field of amino acid-based boron delivery compound development. The primary focus centers on the utilization of the large amino acid transporter 1 (LAT1) as a target for boron carriers in BNCT. The development of efficient carriers remains a critical objective, addressing challenges related to tumor specificity, effective boron delivery, and rapid clearance from normal tissue and blood. LAT1 presents an intriguing and promising target for boron delivery, given its numerous characteristics that make it well suited for drug delivery into tumor tissues, particularly in the case of brain tumors.
| S-EPMC10748186 | biostudies-literature
Project description:Boron neutron capture therapy (BNCT) induces intracellular nuclear reaction to destroy cancer cells during thermal neutron irradiation. To selectively eliminate cancer cells but avoid harmful effects on normal tissues, novel boron-peptide conjugates with angiopep-2, namely ANG-B, were constructed and evaluated in preclinical settings. Boron-peptide conjugates were synthesized using solid-phase peptide synthesis, and the molecular mass was validated by mass spectrometry afterwards. Boron concentrations in 6 cancer cell lines and an intracranial glioma mouse model after treatments were analyzed by inductively coupled plasma atomic emission spectroscopy (ICP-AES). Phenylalanine (BPA) was tested in parallel for comparison. In vitro treatment with boron delivery peptides significantly increased boron uptake in cancer cells. BNCT with 5 mM ANG-B caused 86.5% ± 5.3% of clonogenic cell death, while BPA at the same concentration caused 73.3% ± 6.0% clonogenic cell death. The in vivo effect of ANG-B in an intracranial glioma mouse model was evaluated by PET/CT imaging at 31 days after BNCT. The mouse glioma tumours in the ANG-B-treated group were shrunk by 62.9% on average, while the BPA-treated tumours shrank by only 23.0%. Therefore, ANG-B is an efficient boron delivery agent, which has low cytotoxicity and high tumour-to-blood ratio. Based on these experimental results, we expected that ANG-B may leverage BNCT performance in clinical applications in future.
| S-EPMC10267362 | biostudies-literature
Project description:Boron neutron capture therapy (BNCT) is one of the most appealing radiotherapy modalities, whose localization can be further improved by the employment of boron-containing nanoformulations, but the fabrication of biologically friendly, water-dispersible nanoparticles (NPs) with high boron content and favorable physicochemical characteristics still presents a great challenge. Here, we explore the use of elemental boron (B) NPs (BNPs) fabricated using the methods of pulsed laser ablation in liquids as sensitizers of BNCT. Depending on the conditions of laser-ablative synthesis, the used NPs were amorphous (a-BNPs) or partially crystallized (pc-BNPs) with a mean size of 20 nm or 50 nm, respectively. Both types of BNPs were functionalized with polyethylene glycol polymer to improve colloidal stability and biocompatibility. The NPs did not initiate any toxicity effects up to concentrations of 500 µg/mL, based on the results of MTT and clonogenic assay tests. The cells with BNPs incubated at a 10B concentration of 40 µg/mL were then irradiated with a thermal neutron beam for 30 min. We found that the presence of BNPs led to a radical enhancement in cancer cell death, namely a drop in colony forming capacity of SW-620 cells down to 12.6% and 1.6% for a-BNPs and pc-BNPs, respectively, while the relevant colony-forming capacity for U87 cells dropped down to 17%. The effect of cell irradiation by neutron beam uniquely was negligible under these conditions. Finally, to estimate the dose and regimes of irradiation for future BNCT in vivo tests, we studied the biodistribution of boron under intratumoral administration of BNPs in immunodeficient SCID mice and recorded excellent retention of boron in tumors. The obtained data unambiguously evidenced the effect of a neutron therapy enhancement, which can be attributed to efficient BNP-mediated generation of α-particles.
| S-EPMC10707216 | biostudies-literature
Project description:Boron neutron capture therapy (BNCT) is a biochemically targeted radiotherapy based on the nuclear capture and fission reactions that occur when non-radioactive boron-10, which is a constituent of natural elemental boron, is irradiated with low energy thermal neutrons to yield high linear energy transfer alpha particles and recoiling lithium-7 nuclei. Therefore, BNCT enables the application of a high dose of particle radiation selectively to tumor cells in which boron-10 compound has been accumulated. We applied BNCT using nuclear reactors for 167 cases of malignant brain tumors, including recurrent malignant gliomas, newly diagnosed malignant gliomas, and recurrent high-grade meningiomas from January 2002 to May 2014. Here, we review the principle and history of BNCT. In addition, we introduce fluoride-18-labeled boronophenylalanine positron emission tomography and the clinical results of BNCT for the above-mentioned malignant brain tumors. Finally, we discuss the recent development of accelerators producing epithermal neutron beams. This development could provide an alternative to the current use of specially modified nuclear reactors as a neutron source, and could allow BNCT to be performed in a hospital setting.
| S-EPMC4945594 | biostudies-literature
Project description:Boron neutron capture therapy (BNCT) is a re-emerging therapy with the ability to selectively kill tumor cells. After the boron delivery agents enter the tumor tissue and enrich the tumor cells, the thermal neutrons trigger the fission of the boron atoms, leading to the release of boron atoms and then leading to the release of the α particles (4He) and recoil lithium particles (7Li), along with the production of large amounts of energy in the narrow region. With the advantages of targeted therapy and low toxicity, BNCT has become a unique method in the field of radiotherapy. Since the beginning of the last century, BNCT has been emerging worldwide and gradually developed into a technology for the treatment of glioblastoma multiforme, head and neck cancer, malignant melanoma, and other cancers. At present, how to develop and innovate more efficient boron delivery agents and establish a more accurate boron-dose measurement system have become the problem faced by the development of BNCT. We discuss the use of boron delivery agents over the past several decades and the corresponding clinical trials and preclinical outcomes. Furthermore, the discussion brings recommendations on the future of boron delivery agents and this therapy.
| S-EPMC9009440 | biostudies-literature
Project description:Monodisperse and ultrasmall gadolinium oxide (Gd2O3) nanoparticle colloids (d avg = 1.5 nm) (nanoparticle colloid = nanoparticle coated with hydrophilic ligand) were synthesized and their performance as a multifunctional tumor theragnostic agent was investigated. The aqueous ultrasmall nanoparticle colloidal suspension was stable and non-toxic owing to hydrophilic polyacrylic acid (PAA) coating that was partly conjugated with rhodamine B (Rho) for an additional functionalization (mole ratio of PAA : Rho = 5 : 1). First, the ultrasmall nanoparticle colloids performed well as a powerful T1 magnetic resonance imaging (MRI) contrast agent: they exhibited a very high longitudinal water proton relaxivity (r 1) of 22.6 s-1 mM-1 (r 2/r 1 = 1.3, r 2 = transverse water proton relaxivity), which was ∼6 times higher than those of commercial Gd-chelates, and high positive contrast enhancements in T1 MR images in a nude mouse after intravenous administration. Second, the ultrasmall nanoparticle colloids were applied to gadolinium neutron capture therapy (GdNCT) in vitro and exhibited a significant U87MG tumor cell death (28.1% net value) after thermal neutron beam irradiation, which was 1.75 times higher than that obtained using commercial Gadovist. Third, the ultrasmall nanoparticle colloids exhibited stronger fluorescent intensities in tumor cells than in normal cells owing to conjugated Rho, proving their pH-sensitive fluorescent tumor cell detection ability. All these results together demonstrate that ultrasmall Gd2O3 nanoparticle colloids are the potential multifunctional tumor theragnostic agent.
| S-EPMC9079332 | biostudies-literature
Project description:Highly water dispersible boron based compounds are innovative and advanced materials which can be used in Boron Neutron Capture Therapy for cancer treatment (BNCT). Present study deals with the synthesis of highly water dispersible nanostructured Boron Nitride (BN). Unique and relatively low temperature synthesis route is the soul of present study. The morphological examinations (Scanning/transmission electron microscopy) of synthesized nanostructures showed that they are in transient phase from two dimensional hexagonal sheets to nanotubes. It is also supported by dual energy band gap of these materials calculated from UV- visible spectrum of the material. The theoretically calculated band gap also supports the same (calculated by virtual nano lab Software). X-ray diffraction (XRD) analysis shows that the synthesized material has deformed structure which is further supported by Raman spectroscopy. The structural aspect of high water disperse ability of BN is also studied. The ultra-high disperse ability which is a result of structural deformation make these nanostructures very useful in BNCT. Cytotoxicity studies on various cell lines (Hela(cervical cancer), human embryonic kidney (HEK-293) and human breast adenocarcinoma (MCF-7)) show that the synthesized nanostructures can be used for BNCT.
| S-EPMC5069687 | biostudies-literature