Comparison of Radiation Effects of Gadolinium and Boron Neutron Capture Reactions

Tokuuye, Koichi; Tokita, N.; Akine, Yasuyuki; Nakayama, Hidetsugu; Sakurai, Yoshinori; Kobayashi, Tooru; Kanda, Keiji

doi:10.1007/pl00002332

Cited by 19 publications

(6 citation statements)

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“…In this study, Gd(III) accumulated at 162 ppm intracellularly, calculated on the basis of the 153 Gd radioactivity, in SHIN3 tumors in vivo at 1 day after injection, and 93% of Gd(III) was located in the SHIN3 cells. In a recent study, 400-800 ppm of extracellular Gd(III)-DTPA as well as 30-51 ppm of 10 B was reported as effective to kill cancer cells with neutron beam irradiation (30). Therefore, the concentration of Gd(III) with Av-G6Gd in SHIN3 cells should be adequate for Gd-NCT.…”

Section: Discussionmentioning

confidence: 99%

Avidin-dendrimer-(1B4M-Gd)₂₅₄: A Tumor-Targeting Therapeutic Agent for Gadolinium Neutron Capture Therapy of Intraperitoneal Disseminated Tumor Which Can Be Monitored by MRI

et al. 2001

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Peritoneal carcinomatosis is a late stage in cancer progress, for which no effective therapeutic modality exists. Targeting therapeutic agents to disseminated lesions may be a promising modality for treating peritoneal carcinomatosis. Gadolinium ((157,155)Gd) is known to generate Auger and internal conversion electrons efficiently by irradiation with a neutron beam. Auger electrons from neutron-activated Gd(III) are strongly cytotoxic, but only when Gd(III) atoms have been internalized into the cells. In the present investigation, we have developed a quickly internalizing tumor-targeting system to deliver large quantities of Gd(III) atoms into tumor cells to generate the Auger emission with an external neutron beam. Simultaneously, one would be able to image its biodistribution by MRI with a shortened T1 relaxation time. Avidin-G6-(1B4M-Gd)(254) (Av-G6Gd) was synthesized from generation-6 polyamidoamine dendrimer, biotin, avidin, and 2-(p-isothiocyanatobenzyl)-6-methyl-diethylenetriaminepentaacetic acid (1B4M). The Av-G6Gd was radiolabeled with Gd(III) doped with (153)Gd. All of the 1B4M's on the conjugate were fully saturated with Gd(III) atoms. An in vitro internalization study showed that Av-G6Gd accumulated and was internalized into SHIN3 cells (a human ovarian cancer) 50- and 3.5-fold greater than Gd-DTPA (Magnevist) and G6-(1B4M-Gd)(256) (G6Gd). In addition, accumulation of Gd(III) in the cells was detected by the increased signal on T1-weighted MRI. A biodistribution study was performed in nude mice bearing intraperitoneally disseminated SHIN3 tumors. Av-G6Gd showed specific accumulation in the SHIN3 tumor (103% ID/g) 366- and 3.4-fold greater than Gd-DTPA (0.28% ID/g, p < 0.001) and G6Gd (30% ID/g, p < 0.001) 1 day after i.p. injection. Seventy-eight percent of the tumor-related radioactivity of Av-G6Gd in the SHIN3 tumor was located inside the cells. The SHIN3 tumor-to-normal tissue ratio was greater than 17:1 in all organs and increased up to 638:1 at 1 day after i.p. injection. In conclusion, a sufficient amount (162 ppm) of Av-G6Gd was accumulated and internalized into the SHIN3 cells both in vitro and in vivo to kill the cell using (157/155)Gd with external irradiation with an appropriate neutron beam while monitoring with MRI. Thus, Av-G6Gd may be a promising agent for Gd neutron capture therapy of peritoneal carcinomatosis. This reagent also has the potential to permit monitoring of its pharmacokinetic progress with MRI.

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Section: Discussionmentioning

confidence: 99%

Avidin-dendrimer-(1B4M-Gd)₂₅₄: A Tumor-Targeting Therapeutic Agent for Gadolinium Neutron Capture Therapy of Intraperitoneal Disseminated Tumor Which Can Be Monitored by MRI

et al. 2001

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“…In general, these studies have indicated that folatecoated Gd nanoparticles may have potential of selectively delivering high concentrations of Gd to tumors thereby enhancing the success of NCT. Previous reports have suggested that targeted Gd-NCT strategies may be of therapeutic interest (Akine et al, 1990;Tokuuye et al, 2000). Folate-coated nanoparticles may therefore serve as effective carrier systems for Gd-NCT since (i) nanoparticle size of ∼100 nm could facilitate internalization by tumor cells, (ii) the formulations contain high concentrations of Gd, (iii) nanoparticles may potentially enhance the therapeutic potential Gd-NCT via selective uptake by folate receptors, and (iv) previous studies have shown that presence of Gd in the intracellular space can enhance the therapeutic effectiveness of Gd-NCT (Akine et al, 1990).…”

Section: Synthesis Of Gadolinium Hexanedione (Gdh)mentioning

confidence: 99%

Engineering Tumor-Targeted Gadolinium Hexanedione Nanoparticles for Potential Application in Neutron Capture Therapy

Oyewumi

Mumper

2002

Bioconjugate Chem.

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Microemulsions (oil-in-water) have been employed as templates to engineer nanoparticles containing high concentrations of gadolinium for potential application in neutron capture therapy of tumors. Gadolinium hexanedione (GdH), synthesized by complexation of Gd(3+) with 2,4-hexanedione, was used as the nanoparticle matrix alone or in combination with either emulsifying wax or PEG-400 monostearate. Solid nanoparticles (<125 nm size) were obtained by simple cooling of the microemulsions prepared at 60 degrees C to room temperature in one vessel. The feasibility of tumor targeting via folate receptors was studied. A folate ligand was synthesized by chemically linking folic acid to distearoylphosphatidylethanolamine (DSPE) via a poly(ethylene glycol) (PEG; MW 3350) spacer. To obtain folate-coated nanoparticles, the folate ligand (0.75% w/w to 15% w/w) was added to either the microemulsion templates at 60 degrees C or nanoparticle suspensions at 25 degrees C. Efficiencies of folate ligand attachment/adsorption to nanoparticle formulations were monitored by gel permeation chromatography. Cell uptake studies were carried out in KB cells (human nasopharyngeal epidermal carcinoma cell line), known to overexpress folate receptors. The uptake of folate-coated nanoparticles was about 10-fold higher than uncoated nanoparticles after 30 min at 37 degrees C. The uptake of folate-coated nanoparticles at 4 degrees C was 20-fold lower than the uptake at 37 degrees C and comparable to the uptake of uncoated nanoparticles at 37 degrees C. Folate-mediated endocytosis was further verified by the inhibition of folate-coated nanoparticles uptake by free folic acid. It was observed that folate-coated nanoparticles uptake decreased to approximately 2% of its initial value with the coincubation of 0.001 mM of free folic acid. The results suggested that these tumor-targeted nanoparticles containing high concentrations of Gd may have potential for neutron capture therapy.

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“…The potential for NCT utilizing capture agents other than boron-10 has been studied previously (Tokuyye et al 2000, Miller et al 1993, Masiaskowski et al 1992, Watanabe et al 2002, Allen et al 1989, Maeda et al 1995, Kagehira et al 1994. The neutron interaction characteristics are generally similar between 10 B and 157 Gd, as shown by the total cross sections plotted together in figure 1.…”

Section: Introductionmentioning

confidence: 99%

Computational assessment of improved cell-kill by gadolinium-supplemented boron neutron capture therapy

Culbertson

Jevremović

2003

Phys. Med. Biol.

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Potential improvement in neutron capture therapy (NCT) by utilizing both 157Gd and 10B is assessed considering two parameters calculated in transport models in MCNP4B, the dose to quiescent cells and the therapeutic ratio. Improved sterilization of quiescent or more generally non-uptaking cells is demonstrated with the addition of 157Gd to conventional 10B loading. The improved dose delivery to non-uptaking cells from concurrent administration of 157Gd and 10B is weighed against a second index, degradation in the therapeutic ratio resulting from the longer interaction lengths of the 157Gd capture products. Optimal concentrations of 157Gd are determined considering varying assumptions for boron uptake levels and selectivity. By analysing the dosimetry results of varying 157Gd concentrations applied concurrently with BPA-delivered boron in NCT, this work seeks to determine a balance between the high tumour-specific dose provided by BPA and the high dose to quiescent cells provided by potential gadolinium agents. Depending upon the assumptions for drug specificity, tumour size and fraction of quiescent cells, NCT with low levels of 157Gd (125 microg g(-1)) supplementing 10B loadings was shown to be superior to treatments applying 10B alone.

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Comparison of Radiation Effects of Gadolinium and Boron Neutron Capture Reactions

Cited by 19 publications

References 9 publications

Avidin-dendrimer-(1B4M-Gd)₂₅₄: A Tumor-Targeting Therapeutic Agent for Gadolinium Neutron Capture Therapy of Intraperitoneal Disseminated Tumor Which Can Be Monitored by MRI

Avidin-dendrimer-(1B4M-Gd)₂₅₄: A Tumor-Targeting Therapeutic Agent for Gadolinium Neutron Capture Therapy of Intraperitoneal Disseminated Tumor Which Can Be Monitored by MRI

Engineering Tumor-Targeted Gadolinium Hexanedione Nanoparticles for Potential Application in Neutron Capture Therapy

Computational assessment of improved cell-kill by gadolinium-supplemented boron neutron capture therapy

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Comparison of Radiation Effects of Gadolinium and Boron Neutron Capture Reactions

Cited by 19 publications

References 9 publications

Avidin-dendrimer-(1B4M-Gd)254: A Tumor-Targeting Therapeutic Agent for Gadolinium Neutron Capture Therapy of Intraperitoneal Disseminated Tumor Which Can Be Monitored by MRI

Avidin-dendrimer-(1B4M-Gd)254: A Tumor-Targeting Therapeutic Agent for Gadolinium Neutron Capture Therapy of Intraperitoneal Disseminated Tumor Which Can Be Monitored by MRI

Engineering Tumor-Targeted Gadolinium Hexanedione Nanoparticles for Potential Application in Neutron Capture Therapy

Computational assessment of improved cell-kill by gadolinium-supplemented boron neutron capture therapy

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Product

Resources

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Avidin-dendrimer-(1B4M-Gd)₂₅₄: A Tumor-Targeting Therapeutic Agent for Gadolinium Neutron Capture Therapy of Intraperitoneal Disseminated Tumor Which Can Be Monitored by MRI

Avidin-dendrimer-(1B4M-Gd)₂₅₄: A Tumor-Targeting Therapeutic Agent for Gadolinium Neutron Capture Therapy of Intraperitoneal Disseminated Tumor Which Can Be Monitored by MRI