Selective boron delivery to murine tumors by lipophilic species incorporated in the membranes of unilamellar liposomes.

Abstract

The nido-carborane species K[nido-7-CH3(CH2) tumor/blood boron ratios of -6.Boron neutron capture therapy (BNCT), a binary cancer treatment first proposed by Locher (1) in 1936, is based upon the interaction of two relatively harmless species: a 10B nucleus and a thermal neutron. Capture of the thermal neutron by the 10B nucleus results in the formation of an excited '1B nucleus that decays to yield highly energetic 4He and 7Li products.Each of these fission particles has a range of -10 ,um in tissue, effectively limiting the extent of cellular damage to approximately one cell diameter. Therefore, the selective deposition of 10B nuclei within tumor cells, followed by thermal neutron irradiation, should result in the destruction of tumor cells with little collateral damage to neighboring normal cells. Successful therapy has been calculated to require the selective localization of >15 ,ug of '0B per g of tissue in the tumor mass (2).Higher concentrations of boron are required as the relative distance between the boron target and the tumor cell nucleus increases.The application of BNCT has been thwarted by the paucity of boron compounds that are selectively localized within tumor cells. Equally rare are tumor-selective delivery modalities that deliver boron compounds possessing no inherent tumor specificity themselves (3). Recent studies have reported the selective deposition of boron in EMT6 tumor implants in BALB/c mice using unilamellar liposomes containing encapsulated aqueous solutions of sodium salts of polyhedral borane anionsThe publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.(4, 5). Although these experiments employed injected doses that were relatively low compared with other BNCT delivery modalities (6-11), the liposomes used contained hypertonic ("800 mosM) solutions of borane salts to maximize the boron content of the formulations. The administration of boron with liposomes of this type is limited by the stability of the phospholipid formulations that encapsulate these concentrated ionic polyhedral borane solutions. Furthermore, the preparation of liposomes containing hydrophilic compounds is impeded by the low encapsulation efficiency encountered in the production of small unilamellar vesicles (12). In view of these conditions, the use of lipophilic boron compounds, embedded within the liposome bilayer, provides an attractive method to increase the overall efficiency of incorporation of boroncontaining species, as well as raise the gross boron content of the liposomes in the formulation.

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

“…Liposomes containing MAC embedded in the lipid bilayer were prepared as described in ref. 25. The water-soluble TAC polyhedral borane anion derivative can be incorporated into the interior of the liposome (26).…”

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

“…Boron 10-enriched MAC and TAC were prepared under inert (argon) atmospheres by using methods previously described (21,22,30) and beginning from 10 B-enriched decaborane, with the percentage of 10 B being 95% or greater. Liposome suspensions were created by probe sonication of dried films (300 mg) comprised of 1,2-distearoyl-sn-glycero-3-phosphocholine (Avanti Polar Lipids), cholesterol (Aldrich), and MAC in a 1:1:0.6 molar ratio, respectively, immersed in a hypertonic wetting solution consisting of TAC (250 mM) in 6 mL water.…”

“…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). We demonstrated that inclusion of this amphiphilic nido-carborane in the bilayer yielded selective accumulation of high levels of boron in tumors alone or in combination with encapsulated borane salts (19,30). Furthermore, MAC increases the efficiency of overall liposome uptake by cells.…”

Boron neutron capture therapy assisted by boron-conjugated nanoparticles

“…28 Although the PEGmodified liposomes encapsulating BSH showed higher accumulation in the tumor region than free BSH through the EPR effect, the therapeutic efficacy of the BSH-encapsulated liposomes remains controversial because of the leakage of the encapsulated BSH from the liposome into the blood stream caused by the high ion osmotic pressure of the BSH-loaded interior of the liposome. 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.…”