Liposomes

 

Lipophilic Species for Liposome Bilayer Embedment

          The incorporation of boron-containing species within the liposome bilayer offers the potential for greater efficiency of boron compound incorporation and the production of liposome formulations with much higher boron concentrations. Structurally, these species usually should contain a polar head group and one or two long lipophilic tails. This allows the boron-containing compound to be stably incorporated within the phospholipid membrane at reasonable concentrations without adversely affecting the serum stability of the liposome. The most useful species we have found for this purpose so far is K nido-C2B11H11(CH2)15CH3 (3), whose structure is shown in Figure 4. This carborane derivative can be incorporated into the lipid bilayer at concentrations of 15 mol % without affecting liposome stability or tumor selectivity. Liposomes containing 3 produce a favorable biodistribution when injected in mice, but even better results are obtained with liposomes containing both 3 and 2c (Figure 3B). While both formulations shown in Figure 3 exhibit approximately the same tumor delivery (21% injected dose/g tumor), the additional boron dose provided by the presence of 3 results in an exceptionally high tumor boron concentration of 71 ppm.


                               

                              
Current investigations are directed towards the development of new lipophilic species which may be incorporated within the bilayer at higher concentrations or incorporate much larger boron contents within their structures. One example is the species shown in Figure 5, which consists of a double-tailed lipophilic portion for embedment within the lipid membrane appended to a boron-rich oligophosphate diester (OPD).

New Compounds and Delivery Modalities

          Ongoing and future avenues of research seek to identify new compounds and delivery systems with the potential to contain and deliver greater quantities of boron. For example, new types of liposomes and micelles are being developed which are constructed from boron-containing materials instead of the boron-free phospholipids currently employed. These vesicles, if properly sized, should retain the selectivity and delivery characteristics of standard phospholipid vesicles and carry a much larger quantity of boron to tumor cells. Stable liposomes with suitable dimensions have been produced by the self-assembly of carborane containing ionic surfactants.
          Another methodology under investigation is the use of boron-rich micelles or dendrimers as boron carriers. The closo-B12H122- ion (5) has been hydroxylated to produce derivatives with 1-4 substituents as well as the perhydroxy derivative 7 (closo-B12(OH)122-). As shown in Figure 6, these hydroxyl groups may be converted to a wide variety of useful derivatives through common organic reactions. The resultant species may form the bases for boron-rich 12-fold dendrimers (or molecular micelles) for the delivery of boron.

 

Selected References

T. Peymann A. Herzog, C.B. Knobler, and M.F. Hawthorne, "Aromatic Polyhedral hydroxyborates: bridging boron oxides and boron hydrides," Angew. Chem. Int. Ed.1999, 38, 1062-1064.

T. Peymann, C.B. Knobler, and M.F. Hawthorne, "An icosahedral array of methyl groups supported by an aromatic borane scaffold: the [closo-B12(CH3)12]2- ion," J. Am. Chem. Soc. 1999, 121, 5601-5602.

F. Li, K. Shelly, C.B. Knobler, and M.F. Hawthorne, "A new isomer of the [B20H18]2- ion: synthesis, structure and reactivity of [cis-B20H18]2- and [cis-B20H17NH3]-," Angew. Chem. Int. Ed. 1998, 37, 1868-1871.

R.A. Watson-Clark, M.L. Banquerigo, K. Shelly, M.F. Hawthorne, and E. Brahn, "Model Studies directed toward the application of boron neutron capture therapy to rheumatoid arthritis: boron delivery by liposomes in rat collagen-induced arthritis," Proc. Natl. Acad. Sci. USA1998, 95, 2531-2534.

M.F. Hawthorne and K. Shelly, "Liposomes as drug delivery vehicles for boron agents," J. Neuro-Oncology1997, 33, 55-58.

E.M. Georgiev, K. Shelly, D.A. Feakes, J. Kunyoshi, S. Romano, and M.F. Hawthorne, "Synthesis of amine derivatives of the polyhedral borane anion [B20H18]4-," Inorg. Chem.1996, 35, 5412-5416.

D.A. Feakes, K. Shelly, and M.F. Hawthorne, "Selective boron delivery to murine tumors by lipophilic species incorporated in the membranes of unilamellar liposomes," Proc. Natl. Acad. Sci. USA1995, 92, 1367-1370.

D.A. Feakes, K. Shelly, C.B. Knobler, and M.F. M.F. Hawthorne, "Na3[B20H17NH3]: Synthesis and liposomal delivery to murine tumors," Proc. Natl. Acad. Sci. USA1994, 91, 3029-3033.

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