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The successful treatment of cancer by boron neutron-capture therapy (BNCT) requires the selective concentration of boron-10 within malignant tumors. The potential of liposomes to deliver boron-rich compounds to tumors has been assessed by the examination of the biodistribution of boron delivered by liposomes in tumor-bearing mice. Small unilamellar vesicles with mean diameters of 70 nm or less, composed of a pure synthetic phospholipid (distearoyl phosphatidylcholine) and cholesterol, have been found to stably encapsulate high concentrations of water-soluble ionic boron compounds. The hydrolytically stable borane anions B,.H01, B,2H11SH2-, B20H170H4-B2]HT3, and the normal form and photoisomer of B2oH 2-were encapsulated in liposomes as their soluble sodium salts. The tissue concentration of boron in tumor-bearing mice was measured at several time points over 48 h after i.v. injection of emulsions of liposomes containing the borane anions. Although the boron compounds used do not exhibit an affinity for tumors and are normally rapidly cleared from the body, liposomes were observed to selectively deliver the borane anions to tumors. The highest tumor concentrations achieved reached the therapeutic range (>15 jtg of boron per g of tumor) while maintaining high tumor-boron/blood-boron ratios (>3). The most favorable results were obtained with the two isomers of B2OH _. These boron compounds have the capability to react with intracellular components after they have been deposited within tumor cells by the liposome, thereby preventing the borane ion from being released into blood.Boron neutron-capture therapy (BNCT), first proposed by Locher in 1936 (1), is based upon the propensity of the 10B nucleus to undergo the 10B + 1n -* 'Li + 'He reaction with thermal neutrons. This process releases 2.28 MeV of kinetic energy, which is distributed between the a-particle and the 7Li+ ion. The effective distance of travel of these two ions in tissue is limited to approximately one cell diameter. During their passage through the interior of a cell, the energetic fission products cause ionization-tracking and cellular damage with associated cytotoxicity. Since the neutron capture cross-section of the 10B nucleus is 103 to 104 greater than that of all elements of physiological importance, the selective concentration of 10B atoms within cancer cells, followed by irradiation with thermal neutrons, should result in the destruction of the tumor cells even in the presence of neighboring normal cells.The development of effective targeting strategies for the selective transport ofboron to cancer cells has been the single most urgent problem in the area of BNCT. Successful therapy requires the site-specific delivery of relatively large amounts (15-20 jig of B per g of tissue) of boron to tumors (2). Strategies employed have included the use of boron compounds with some natural affinity for tumors, such as 4-(dihydroxyboryl)phenylalanine (BPA) (3) or the mercaptoundecahydro-closo-dodecaborate dianion (B12H,,SH2-; BSH) (4); the attac...

The polyhedral borane ion [n-B2,HlaJs reacts with liquid ammonia in the presence of a suitable base to produce an apical-equatorial (ae) Isomer of the [B, [1][2])-2-NHIE3BIep3. The structure of this product has been confire by "B NMR c opy and x-ray c lgraphy. This spe undergoes acid-catalyzed rearrangement to an apical-apical (ae) isomer, [1-(1'-B1JHI)-2-NHI3BJhs]P-, whose structure has been determined by "1B NMR spectroscopy. The Successful application of BNCT depends on the identification of boron compounds, such as boron-conjugated porphyrins (2), that possess a natural mechanism for tumor cell accretion or, alternatively, a tumor-specific delivery modality through which compounds rich in boron may be specifically delivered to tumor cells. The use of tumor-specific delivery modalities, such as tumor-targeted monoclonal antibody conjugates, has thus far been limited by the highly competitive loss of conjugate to liver once therapeutically effective amounts of boron have been conjugated to the antibody (3).The ideal delivery mechanism should be able to incorporate large quantities of boron without affecting its selective delivery of boron to the tumor. Small unilamellar liposomes encapsulating concentrated aqueous solutions of polyhedral borane salts and injected intravenously have been shown to deliver therapeutic quantities of boron selectively to tumors in vivo (4).

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.

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Among the polyhedral [closo-BnHn]2- ion series (n = 5-12 inclusive) the aromatic [closo-B10H10]2- ion is both readily available and quite reactive. Among its many reactions which retain its cage structure one finds the oxidative dimerization reaction in which two [closo-B10H12]2- ions each formally lose a hydride ion and undergo dimerization of the resulting [closo-B10H9]- ions to produce the [trans-B20H18]2- ion. The two-component [closo-B10H9]- ions of the latter are linked together by a pair of unique B-B-B bonds which provide unprecedented reactivity to the structure. Among these reactions are the two-electron reduction to a set of three interconvertible [B20H18]4- ions having intercage B-B bonds and the related reductive substitution reaction in which [trans-B20H18]2- undergoes attack by nucleophile, L, to produce [B20H18L]2-. The latter species is formally a substituted [B20H19]3- (L = H) ion formed by B-B bond protonation of one of the isomeric [B20H18]4- ions. These and a variety of novel reactions are described here along with interrelated reaction mechanisms considered for the first time.

The application of boron neutron capture therapy to rheumatoid arthritis requires the selective delivery of the boron-10 isotope to the synovitic tissue. The use of liposomes as a boron delivery method has been explored through the measurement of the time course biodistribution of boron in rats with collagen-induced arthritis (CIA). In an attempt to increase the synovium͞blood boron ratio by lowering the blood boron concentration, a liposomal formulation characterized by a shorter blood clearance time was examined. Thus, the biodistribution of liposomes with additional K[nido-7-CH 3 (CH 2 ) 15 -7,8-C 2 B 9 H 11 ] incorporated in the vesicle membrane not only demonstrated more rapid blood clearance and slightly higher synovium͞blood boron ratios but also exhibited reduced boron uptake in synovial tissue. These studies with boron neutron capture therapy for CIA suggest that this form of therapy may be feasible in the treatment of rheumatoid arthritis.

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