Model studies directed toward the application of boron neutron capture therapy to rheumatoid arthritis: Boron delivery by liposomes in rat collagen-induced arthritis

The possible role of vascular endothelial cell damage in the loss of intestinal crypt stem cells and the subsequent development of the gastrointestinal (GI) syndrome is addressed. Mice received wholebody epithermal neutron irradiation at a dose rate of 0.57 ؎ 0.04 Gy⅐min ؊1 . An additional dose was selectively targeted to endothelial cells from the short-ranged (5-9 m) particles released from neutron capture reactions in 10 B confined to the blood by incorporation into liposomes 70 -90 nm in diameter. Different liposome formulations produced 45 ؎ 7 or 118 ؎ 12 g͞g 10 B in the blood at the time of neutron irradiation, which resulted in total absorbed dose rates in the endothelial cells of 1.08 ؎ 0.09 or 1.90 ؎ 0.16 Gy⅐min ؊1 , respectively. At 3.5 d after irradiation, the intestinal crypt microcolony assay showed that the 2-to 3-fold increased doses to the microvasculature, relative to the nonspecific wholebody neutron beam doses, caused no additional crypt stem cell loss beyond that produced by the neutron beam alone. The threshold dose for death from the GI syndrome after neutron-beam-only irradiation was 9.0 ؎ 0.6 Gy. There were no deaths from the GI syndrome, despite calculated absorbed doses to endothelial cells as high as 27.7 Gy, in the groups that received neutron beam doses of <9.0 Gy with boronated liposomes in the blood. These data indicate that endothelial cell damage is not causative in the loss of intestinal crypt stem cells and the eventual development of the GI syndrome.gastrointestinal syndrome ͉ boron ͉ liposomes ͉ neutron capture R adiation-induced changes seen in normal tissues are traditionally separated into early and late effects. Stem-cellbased, rapidly renewing normal tissues, such as the bone marrow and the intestinal epithelium, are early responding tissues in which the time courses of the radiation syndromes are directly related to the turnover time of the differentiated functional cell compartments. The intestinal stem cells reside in the crypts of Lieberkühn at the base of the finger-like villi that comprise the intestinal epithelium. Epithelial cells differentiate as they migrate up the crypt and the villus and are eventually sloughed off at the tip into the intestinal lumen: the transit time takes Ϸ3-4

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“…MACϩTAC liposomes were prepared as described in ref. 27. All boron compounds were enriched in the 10 B isotope to Ͼ98%.…”

Section: Methodsmentioning

confidence: 99%

Selective irradiation of the vascular endothelium has no effect on the survival of murine intestinal crypt stem cells

Schuller¹,

Binns

Riley

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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“…These times were selected based on a previous study in experimental mammary adenocarcinoma in BALB/c mice (Feakes et al 1995) and are considerably longer than the 3-4 h intervals characteristically used for low molecular weight, non-encapsulated boron carriers such as BPA and GB-10. As mentioned above, in the case of liposomes, transport out of the circulation into tumor tissue is favored by the leaky tumor neovasculature (Watson-Clark et al 1998) and would take longer than the diffusion out of the circulation of free, low molecular weight boron compounds (Barth et al 2005). The known enhanced permeability and retention (EPR) effect in tumors (Maeda and Matsumura 1986) and the longer circulation life span of an encapsulated drug would allow for the slow build-up of tumor boron concentration in the case of liposomes.…”

Section: Blood and Tissue Samplingmentioning

confidence: 96%

Boron delivery with liposomes for boron neutron capture therapy (BNCT): biodistribution studies in an experimental model of oral cancer demonstrating therapeutic potential

Heber

Kueffer

Lee

et al. 2012

Radiat Environ Biophys

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Boron neutron capture therapy (BNCT) combines selective accumulation of (10)B carriers in tumor tissue with subsequent neutron irradiation. We previously demonstrated the therapeutic efficacy of BNCT in the hamster cheek pouch oral cancer model. Optimization of BNCT depends largely on improving boron targeting to tumor cells. Seeking to maximize the potential of BNCT for the treatment for head and neck cancer, the aim of the present study was to perform boron biodistribution studies in the oral cancer model employing two different liposome formulations that were previously tested for a different pathology, i.e., in experimental mammary carcinoma in BALB/c mice: (1) MAC: liposomes incorporating K[nido-7-CH(3)(CH(2))(15)-7,8-C(2)B(9)H(11)] in the bilayer membrane and encapsulating a hypertonic buffer, administered intravenously at 6 mg B per kg body weight, and (2) MAC-TAC: liposomes incorporating K[nido-7-CH(3)(CH(2))(15)-7,8-C(2)B(9)H(11)] in the bilayer membrane and encapsulating a concentrated aqueous solution of the hydrophilic species Na(3) [ae-B(20)H(17)NH(3)], administered intravenously at 18 mg B per kg body weight. Samples of tumor, precancerous and normal pouch tissue, spleen, liver, kidney, and blood were taken at different times post-administration and processed to measure boron content by inductively coupled plasma mass spectrometry. No ostensible clinical toxic effects were observed with the selected formulations. Both MAC and MAC-TAC delivered boron selectively to tumor tissue. Absolute tumor values for MAC-TAC peaked to 66.6 ± 16.1 ppm at 48 h and to 43.9 ± 17.6 ppm at 54 h with very favorable ratios of tumor boron relative to precancerous and normal tissue, making these protocols particularly worthy of radiobiological assessment. Boron concentration values obtained would result in therapeutic BNCT doses in tumor without exceeding radiotolerance in precancerous/normal tissue at the thermal neutron facility at RA-3.

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“…[139] The boron neutron capture reaction could be used to selectively ablate arthritic tissue, without causing damage to other tissue and/organs, so long as highly selective and efficient boron delivery vehicles could be developed. [140][141][142] …”

Section: Boron Neutron Capture Synovectomymentioning

confidence: 98%

Polyhedral Boranes for Medical Applications: Current Status and Perspectives

2009

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Model studies directed toward the application of boron neutron capture therapy to rheumatoid arthritis: Boron delivery by liposomes in rat collagen-induced arthritis

Cited by 68 publications

References 12 publications

Selective irradiation of the vascular endothelium has no effect on the survival of murine intestinal crypt stem cells

Selective irradiation of the vascular endothelium has no effect on the survival of murine intestinal crypt stem cells

Boron delivery with liposomes for boron neutron capture therapy (BNCT): biodistribution studies in an experimental model of oral cancer demonstrating therapeutic potential

Polyhedral Boranes for Medical Applications: Current Status and Perspectives

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