Camouflaged Carboranes and Polyhedral Boranes

          Thus far, "camouflaged carboranes and polyhedral boranes" are comprised of derivatives of the three isomers of carboranes (1,2- or ortho-, 1,7- or meta-, and 1,12- or para-carborane) and the icosahedral B₁₂H₁₂^2- anion. The term "camouflaged" carborane or polyhedral borane describes a molecule in which all, or very nearly all, the B-H vertices have been substituted by hydrophobic alkyl or hydrophilic hydroxyl groups. The resulting polyhedral borane derivative, which has a borane core stabilized by multicenter electron delocalization, is shrouded by a sheath of substituents which display characteristic properties. Hence, camouflaged polymethylated carboranes and B₁₂H₁₂^2- species demonstrate physical and chemical properties representative of both the thermally and chemically stable carboranes or polyhedral boranes and the versatile aliphatic hydrocarbons. These unprecedented structures appear at first sight to be either a hydrophobic hydrocarbon (methyl groups on the icosahedral surface) or a hydrophilic sugar (hydroxyl groups on the icosahedral surface). Such camouflaged species are currently being investigated as modules for the formation of the functional assemblies discussed above. Also, both of these unusual families may be derivatized and incorporated in new pharmaceuticals, employed as dendrimer (closomer) precursors, as drug delivery vehicles and in various aspects of nanotechnology. Structural variations, including stereochemistry, are unlimited and the uses to which new materials may be put are similarly broad. Another useful feature of the polyhedral boranes and carboranes is again emphasized: their inertness to enzymatic attack in marked contrast to purely organic species.

Oligomeric Phosphate Diesters

          A wide variety of boron-rich molecules have been synthesized for use as boron-delivery agents to provide target atoms for the boron neutron capture therapy (BNCT) of cancer. This promising method for the treatment of various types of cancer is dependent upon the ability of boron-containing compounds to preferentially accumulate in tumor tissue. Selective tumor cell penetration followed by nuclear localization of boron-rich agents will greatly enhance the efficiency of this potential therapy. A family of promising nuclear delivery agents is the carborane-containing oligomeric phosphate diesters (OPDs). These boron-rich molecules mimic the primary structure of DNA: instead of nucleosides connected by phosphodiester linkages, OPDs consist of closo- or nido- carborane modules connected by phosphodiester linkages. The nido-OPD derivatives have been demonstrated to localize and persist inside cell nuclei (10⁹ boron atoms/cell) without incurring cell death. The observed intracellular binding of dinegative nido-OPD modules may be the result of their coulombic interaction with positively charged histones in the cell nuclei. This important discovery opens new opportunities for improving BNCT and provides a new vehicle for delivering molecules such as toxins or fragments of DNA to cell nuclei. Other non-cytotoxic enzyme-resistant nuclear delivery systems are unknown. In order to utilize OPDs in selective cell-killing, the OPDs must first be directed to the targeted cells. This may be accomplished by attaching the OPDs to biomolecules which are themselves selectively targeted for cancer cells. These OPD-biomolecule conjugates will then accumulate within the targeted tumor cells. Alternatively, OPDs can be selectively localized in tumor cells using liposomes as delivery vehicles, as discussed below.

Exploratory Liposome Research

          One of the most challenging problems facing the successful application of BNCT is the development of effective drug-targeting strategies which provide tumor-selective delivery of therapeutic quantities of boron or neutrons. The simplest approach is to use a tumor-targeted high energy neutron beam and global agents, small boron-containing molecules with little tumor-selectivity. Such agents are easy to prepare, relatively non-toxic, and they can be administered in large doses. At the other end of the spectrum are big, complex, boron-rich molecules such as tumor-cell targeting biomolecule conjugates of OPDs which potentially exhibit greater tumor-selectivity while carrying large quantities of boron per molecule. However, species of this sort have always fallen short of expectations and they no longer are considered as viable delivery vehicles. Consequently, another type of agent was explored.
          In terms of cell selectivity and delivery capability, unilamellar liposomes lie somewhere between the extremes of global and tumor-selective delivery and combine some of the more attractive qualities of both methods. As employed here, liposomes are small spheroidal phospholipid vesicles which can be used to transport a variety of boron-containing compounds into the interior of tumor cells. Since significant tumor cell-selectivity is provided by the liposome vehicle, the boron species employed may be relatively simple and dissolved in the aqueous core of the vesicle, embedded within the phospholipid bilayer, or both. The observed selectivity is due in part to the small size of the liposome nanoparticle (50-100 nm), but this is quite large in molecular terms. Consequently, the vesicle may carry a large boron dose. In addition, encapsulation of the boron species within a liposome attenuates potential systemic toxicity and provides an extended circulation lifetime in vivo. Very promising results have been obtained from investigations with boron-laden liposomes in animal tumor models evaluated for us in other laboratories.

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