Liposomes

          The successful application of boron neutron capture therapy (BNCT) for cancer requires the preferential concentration of significant quantities of the stable ¹⁰B isotope within tumors over normal healthy tissues. The slow evolution of effective drug-targeting methodologies for the selective delivery of sufficient amounts of boron to cancer cells remains as an important obstacle to the development of this therapy.
          The goal of the liposome project is to develop drug delivery modalities consisting of liposomes (or other carriers such as micelles) which contain, or are constructed from, boron-containing compounds. This is accomplished through a) the identification and synthesis of appropriate hydrophilic and lipophilic boron agents; b) the incorporation of the candidate compounds within small unilamellar vesicles (SUVs) or similar delivery vehicles; and c) the evaluation of these preparations in boron biodistribution experiments using animal models.

          Small unilamellar liposomes (Figure 1) composed of the phospholipid DSPC and cholesterol have been shown to be a viable transport modality for the selective, intracellular delivery of boron-containing compounds to neoplastic tissues. This was demonstrated through boron biodistribution experiments which typically employed BALB/c mice bearing subcutaneous EMT6 (mammary adenocarcinoma) tumors. There are two ways that SUVs may be employed as boron carriers: water-soluble boron compounds are encapsulated within the aqueous core of the liposome, or lipophilic boron compounds are embedded within the phospholipid bilayer which defines the liposome structure. In addition, both types of boron compounds may be combined within the same liposomal formulation.
          Current research is focused primarily on the identification of superior boron compound candidates for the liposome-mediated delivery of boron to tumors for application in BNCT. In addition, the development of new boron-containing materials for the construction of liposomes, micelles, and dendrimers is being investigated as a means to increase the quantity and selectivity of boron delivery. Finally, the utility of these delivery systems is being investigated for application to a variety of therapeutic targets including head and neck tumors, non-small cell lung cancer, and rheumatoid arthritis.

Hydrophilic Species for Liposome Encapsulation     
    
           Hydrophilic boron compounds for encapsulation within liposomes must be highly water-soluble, hydrolytically stable, and have a high boron content. Furthermore, good results are obtained only when the boron-containing species includes a functional group or reactive polyhedral borane structure with the potential to combine with intracellular components, thus providing an anchor for the tumor retention of boron after initial liposomal delivery. Most investigations have employed species derived from the closo-B₁₂H₁₂^2-, closo-B₁₀H₁₀^2-, and trans-B₂₀H₁₈^2- (1) cage systems. The most successful hydrophilic boron compounds investigated have been derivatives of a²-B₂₀H₁₈^4-, which are easily prepared from 1 (Figure 2), have a high boron content, and often exhibit favorable tumor retention due to the reactivity provided by the polyhedral structure. The reactivity of 1 permits the production of a wide variety of such derivatives. In particular, the amine derivatives a²-B₂₀H₁₇NH₂R^3- (2, R = H, Pr, CH₂CH₂NH₂) have demonstrated excellent biodistribution results. When injected in tumor-bearing mice (Figure 3A), liposomes containing a²-B₂₀H₁₇NH₂CH₂CH₂NH₂^3- (2c) produced therapeutically useful boron concentrations in tumor (38 ppm at 30 h) with good selectivity (tumor/blood boron ratio >3).

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