Unilamellar Liposomes with Enhanced Boron Content

Li, Tiejun; Hamdi, Julie; Hawthorne, M. Frederick

doi:10.1021/bc0501350

Cited by 74 publications

(57 citation statements)

References 26 publications

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“…It should be noted that the 10 B-enriched PM and the 10 B-enriched NPM caused no acute toxicity, even at a dose of 15.6 mg B per kg, although the previously reported liposomes composed of nido-carborane conjugated lipids showed acute toxicity within one day at a dose of 6.0 mg B per kg. 31 These facts strongly indicate that the 10 B-enriched PM surpass the liposomes composed of nido-carborane conjugated lipids as boron carriers for BNCT from the standpoint of toxicity. On the basis of these results, we conclude that the 10 B-enriched PM are suitable candidates for boron carriers in cancer BNCT, and that they exhibit beneficial therapeutic effects without any side effects.…”

Section: Core-polymerized and Boron-conjugated Micellesmentioning

confidence: 94%

“…29 An alternative approach is represented by the 10 B-compound-conjugated liposomes fabricated by covalently linking a lipid (hydrophobic group) with a 10 B-compound (hydrophilic group) to suppress the leakage of the 10 B-compound into the bloodstream. 30,31 The 10 B-compoundconjugated liposome achieved a sufficient high 10 B concentration in the tumor, but the synthesis of the nido-carborane required complicated preparation steps. Additionally, serious acute toxicity was observed in vivo due to the cytotoxicity of nido-carborane, producing acute toxicity within one day at a dose of 6.0 mg boron per kg.…”

Section: Introductionmentioning

confidence: 99%

“…Additionally, serious acute toxicity was observed in vivo due to the cytotoxicity of nido-carborane, producing acute toxicity within one day at a dose of 6.0 mg boron per kg. 31 Nakamura et al 32,33 developed 10 B-compound-conjugated liposomes using lipids that link with 10 B-enriched BSH by covalent bonds to reduce the cytotoxicity of the boron-conjugated liposomes. However, the 10 B-enriched BSH-conjugated liposomes exhibited a short retention time in tumor tissues that was most likely caused by the insufficient stability of the liposomes.…”

Section: Introductionmentioning

confidence: 99%

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Boron neutron capture therapy assisted by boron-conjugated nanoparticles

Sumitani

Nagasaki

2012

Polym J

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For high-performance boron neutron capture therapy (BNCT), core-shell-type biodegradable nanoparticles possessing boron clusters in their cores are designed to improve their accumulation tendency in the tumor region. The copolymerization of styrene carrying carborane with a poly(ethylene glycol)-block-poly(lactide) copolymer (PEG-b-PLA) that possesses an acetal group at its PEG end and a methacryloyl group at its PLA end (acetal-PEG-b-PLA-MA) was performed in an aqueous medium. As the acetal-PEG-b-PLA-MA forms a polymeric micelle in an aqueous medium, the carborane monomer in the hydrophobic core is solubilized, and the carborane in the core of the micelle is given covalent conjunction. Two carborane compounds, carborane with a mono-vinylbenzyl group [1-(4-vinylbenzyl)-closo-carborane (VB-carborane)] and carborane with di-vinylbenzyl groups [1,2-bis(4-vinylbenzyl)-closo-carborane ((VB) 2 -carborane)], were newly prepared and employed for the core polymerizations. The encapsulation efficiency of the VB-carborane in the micelles is much higher than that of the (VB) 2 -carborane. This improved efficiency is most likely caused by the interaction of the hydrogen bonding of the VB-carborane with the polymer micelle matrix, while no hydrogen bonding sites remain in the case of the (VB) 2 -carborane. The obtained corepolymerized and boron-conjugated micelles (PM, which were prepared from VB-carborane) showed extremely high stability under physiological conditions, which suppressed the leakage of boron compounds owing to the existence of the covalent bonds. The accumulation of the PM (7.2 ID% per g) in tumors is much higher than that of the non-polymerized micelles (NPM) (0.7 ID% per g) under the same conditions (at 24 h after injection) because of the enhanced stability of the micelles under physiological conditions. In addition, thermal neutron irradiation experiments indicated significant suppression of the growth of tumor volume in tumor-bearing mice treated with the PM. It is important to note that the PM administered via intravenous injection were excreted almost completely from the major organs, except for the tumor, after a week. Therefore, these boronconjugated micelles represent a promising approach to the creation of a novel boron carrier for BNCT.

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Section: Core-polymerized and Boron-conjugated Micellesmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Boron neutron capture therapy assisted by boron-conjugated nanoparticles

Sumitani

Nagasaki

2012

Polym J

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“…[5][6][7][8][9][10][11] The lipids should be ideal carriers of boron when incorporated into liposomes, especially when the liposomes carry a targeting unit such as transferrin or other suitable agents. 12 Liposomes made from boron-containing lipids can carry at least the same amount of boron as lipids into which watersoluble boron compounds are encapsulated.…”

Section: Schaffran Et Almentioning

confidence: 99%

Hemorrhage in mouse tumors induced by dodecaborate cluster lipids intended for boron neutron capture therapy

Schaffran¹,

Jiang²,

Bergmann³

et al. 2014

IJN

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The potential of boron-containing lipids with three different structures, which were intended for use in boron neutron capture therapy, was investigated. All three types of boron lipids contained the anionic dodecaborate cluster as the headgroup. Their effects on two different tumor models in mice following intravenous injection were tested; for this, liposomes with boron lipid, distearoyl phosphatidylcholine, and cholesterol as helper lipids, and containing a polyethylene glycol lipid for steric protection, were administered intravenously into tumor-bearing mice (C3H mice for SCCVII squamous cell carcinoma and BALB/c mice for CT26/WT colon carcinoma). With the exception of one lipid (B-THF-14), the lipids were well tolerated, and no other animal was lost due to systemic toxicity. The lipid which led to death was not found to be much more toxic in cell culture than the other boron lipids. All of the lipids that were well tolerated showed hemorrhage in both tumor models within a few hours after administration. The hemorrhage could be seen by in vivo magnetic resonance and histology, and was found to occur within a few hours. The degree of hemorrhage depended on the amount of boron administered and on the tumor model. The observed unwanted effect of the lipids precludes their use in boron neutron capture therapy.

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“…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

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

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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

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Unilamellar Liposomes with Enhanced Boron Content

Cited by 74 publications

References 26 publications

Boron neutron capture therapy assisted by boron-conjugated nanoparticles

Boron neutron capture therapy assisted by boron-conjugated nanoparticles

Hemorrhage in mouse tumors induced by dodecaborate cluster lipids intended for boron neutron capture therapy

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

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