Boron-Containing Compounds for Liposome-Mediated Tumor Localization and Application to Neutron Capture Therapy

Technical Report · Thu Apr 07 00:00:00 EDT 2005

DOI:https://doi.org/10.2172/838435· OSTI ID:838435

Hawthorne, M. Frederick ^[1]

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1. Univ. of California, Los Angeles, CA (United States)

Medical application of boron neutron capture therapy (BNCT) has been significantly hindered by the slow development of boron drug-targeting methodologies for the selective delivery of high boron concentration sto malignant cells. We have successfully sought to fill this need by creating liposomes suitable as in vivo boron delivery vehicles for BNCT. Delivery of therapeutic quantities of boron to tumors in murine models has been achieved with small unilamellar boron-rich liposomes. Subsequently, attempts have been made to improve delivery efficiency of liposomes encapsulating boron-containing water-soluble species into their hollow core by incorporating lipophilic boron compounds as addenda to the liposome bilayer, incorporating boron compounds as structural components of the bilayer (which however, poses the risk of sacrificing some stability), and combinations thereof. Regardless of the method, approximately 90% of the total liposome mass remains therapeutically inactive and comprised of the vehicle's construction materials, while less than 5% is boron for neutron targeting. Following this laboratory's intensive study, the observed tumor specificity of certain liposomes has been attributed to their diminutive size of these liposomes (30-150 nm), which enables these small vesicles to pass through the porous, immature vasculature of rapidly growing tumor tissue. We surmised that any amphiphilic nanoparticle of suitable size could possess some tumor selectivity. Consequently, the discovery of a very boron-rich nanoparticle delivery agent with biodistribution performance similar to unilamellar liposomes became one of our goals. Closomers, a new class of polyhedral borane derivatives, attracted us as an alternative BNCT drug-delivery system. We specifically envisioned dodeca (nido-carboranyl)-substituted closomers as possibly having a great potential role in BNCT drug delivery. They could function as extraordinarily boron-rich BNCT drugs since they are amphiphilic unimolecular nanoparticles presenting several advantages: tunable size through functionalization and branching, spherical shape due to the icosahedral B122 core, promising water solubility resulting from degradation of all pendant closo-carborane groups to their hydrophilic nido anion substituents, and efficient boron delivery owing to the presence of 120 boron atoms which gives rise to a boron content as high as 40% by weight. Keeping the new objective in mind, we have focused on the design, synthesis and evaluation of new and very boron-rich closomer species. Additionally, progress has also been made toward the evaluation of a newly synthesized boron-rich lipid as a substitute for DSPC in bilayer construction, and the boron content of the resulting liposomes has been greatly enhanced. Related research involving the synthesis and self-assembly of carborane-containing amphiphiles has been systematically studied. Combined hydrophobic and hydrophilic properties of the single-chain amphiphiles allow their spontaneous self-assembly to form rods under a variety of variable conditions, such as concentration in the bilayer, carborane cage structure, chain-length, counterion identity, solvents, methods of preparation, and the ionic charge. On the other hand, the number of attached chains affects the self-assembly process. Particles having totally different shapes have been observed for dual-chain amphiphiles.

• Research Organization: University of California Los Angeles, CA (United States)
• Sponsoring Organization: USDOE Office of Science (SC)
• DOE Contract Number: FG03-95ER61975
• OSTI ID: 838435
• Report Number(s): DOE/ER/61975-F; TRN: US1003103
• Country of Publication: United States
• Language: English

Related Subjects

37 INORGANIC
ORGANIC
PHYSICAL AND ANALYTICAL CHEMISTRY
54 ENVIRONMENTAL SCIENCES
59 BASIC BIOLOGICAL SCIENCES
ANIONS
ATOMS
BORANES
BORON
BORON COMPOUNDS
CARBORANES
CONSTRUCTION
EFFICIENCY
IN VIVO
LIPIDS
LIPOSOMES
NEOPLASMS
NEUTRON CAPTURE THERAPY
NEUTRONS
SOLUBILITY
SOLVENTS
SYNTHESIS
WATER
Boranes
Carboranes
Liposomes
Closomers
Nanoparticles