Na3[B20H17NH3]: synthesis and liposomal delivery to murine tumors.

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

“…25. The water-soluble TAC polyhedral borane anion derivative can be incorporated into the interior of the liposome (26). MACϩTAC liposomes were prepared as described in ref.…”

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

“…Evidence suggests that the persistence of TAC in the tumor is a result of covalent bond formation with nucleophiles present on endogenous intracellular proteins (21)(22)(23)(24)(25)(26)(27) (Fig. 1 − (25)(26)(27), which is readily produced in oxidizing environments like those often possessed by tumor cell interiors (28,29).…”

mentioning

confidence: 99%

“…The (21). Evidence suggests that the persistence of TAC in the tumor is a result of covalent bond formation with nucleophiles present on endogenous intracellular proteins (21)(22)(23)(24)(25)(26)(27) (Fig.…”

mentioning

confidence: 99%

“…An inherent drawback in the preparation of small unilamellar liposomes is that only a small percentage of the total solution containing a BNCT agent is encapsulated, limiting the amount of boron that can be delivered to tumors via the liposomal interior alone (21). To ameliorate this issue, our laboratory devised a complementary lipophilic agent, K[nido-7-CH 3 (CH 2 ) 15 -7,8-C 2 B 9 H 11 ] (MAC), which is stably incorporated into the liposome bilayer (30).…”

mentioning

confidence: 99%

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Boron neutron capture therapy demonstrated in mice bearing EMT6 tumors following selective delivery of boron by rationally designed liposomes

Kueffer

Maitz

Khan

et al. 2013

119

100

The application of boron neutron capture therapy (BNCT) following liposomal delivery of a 10 B-enriched polyhedral borane and a carborane against mouse mammary adenocarcinoma solid tumors was investigated. Unilamellar liposomes with a mean diameter of 134 nm or less, composed of an equimolar mixture of cholesterol and 1,2-distearoyl- sn -glycero-3-phosphocholine and incorporating Na 3 [1-(2′-B 10 H 9 )-2-NH 3 B 10 H 8 ] in the aqueous interior and K[ nido -7-CH 3 (CH 2 ) 15 -7,8-C 2 B 9 H 11 ] in the bilayer, were injected into the tail veins of female BALB/c mice bearing right flank EMT6 tumors. Biodistribution studies indicated that two identical injections given 24 h apart resulted in tumor boron levels exceeding 67 µg/g tumor at 54 h—with tumor/blood boron ratios being greatest at 96 h (5.68:1; 43 µg boron/g tumor)—following the initial injection. For BNCT experiments, tumor-bearing mice were irradiated 54 h after the initial injection for 30 min with thermal neutrons, resulting in a total fluence of 1.6 × 10 12 neutrons per cm 2 (±7%). Significant suppression of tumor growth was observed in mice given BNCT vs. control mice (only 424% increase in tumor volume at 14 d post irradiation vs. 1551% in untreated controls). In a separate experiment in which mice were given a second injection/irradiation treatment 7 d after the first, the tumor growth was vastly diminished (186% tumor volume increase at 14 d). A similar response was obtained for mice irradiated for 60 min (169% increase at 14 d), suggesting that neutron fluence was the limiting factor controlling BNCT efficacy in this study.

“…Small liposomes (<100 nm) pass through aberrant tumor vessels (17) and passively accumulate by the enhanced permeability and retention effect (18,19). Small unilamellar liposomes in particular are viewed as potentially useful boron delivery vehicles for BNCT and have been extensively studied by Hawthorne and coworkers (20)(21)(22)(23)(24)(25)(26) and other groups (27)(28)(29) (26).…”

mentioning

confidence: 99%

Therapeutic efficacy of boron neutron capture therapy mediated by boron-rich liposomes for oral cancer in the hamster cheek pouch model

Heber

Hawthorne

Kueffer

et al. 2014

The application of boron neutron capture therapy (BNCT) mediated by liposomes containing 10 B-enriched polyhedral borane and carborane derivatives for the treatment of head and neck cancer in the hamster cheek pouch oral cancer model is presented. These liposomes are composed of an equimolar ratio of cholesterol and 1,2-distearoyl-sn-glycero-3-phosphocholine, incorporating K[nido-7-CH 3 (CH 2 ) 15 -7,8-C 2 B 9 H 11 ] (MAC) in the bilayer membrane while encapsulating the hydrophilic species Na 3 [ae-B 20 H 17 NH 3 ] (TAC) in the aqueous core. Unilamellar liposomes with a mean diameter of 83 nm were administered i.v. in hamsters. After 48 h, the boron concentration in tumors was 67 ± 16 ppm whereas the precancerous tissue contained 11 ± 6 ppm, and the tumor/normal pouch tissue boron concentration ratio was 10:1. Neutron irradiation giving a 5-Gy dose to precancerous tissue (corresponding to 21 Gy in tumor) resulted in an overall tumor response (OR) of 70% after a 4-wk posttreatment period. In contrast, the beam-only protocol gave an OR rate of only 28%. Once-repeated BNCT treatment with readministration of liposomes at an interval of 4, 6, or 8 wk resulted in OR rates of 70-88%, of which the complete response ranged from 37% to 52%. Because of the good therapeutic outcome, it was possible to extend the follow-up of BNCT treatment groups to 16 wk after the first treatment. No radiotoxicity to normal tissue was observed. A salient advantage of these liposomes was that only mild mucositis was observed in dose-limiting precancerous tissue with a sustained tumor response of 70-88%.oncology | cancer | boronated liposomes | BNCT | neutron radiation