The long term objective of this research is to utilize low density lipoprotein (LDL) to microinject bron compounds into malignant cells through site specific recognition and endocytosis of LDL particles. To accomplish this, sixty-seven hydrophobic molecules which contain the boron compound 1,2-dicarbaclosododecaborane (1,2-B10H10C2H2) will be synthesized, reconstituted into human LDL, and the resultting boronated LDLs evaluated for site specific delivery in cell culture systems. The use of boron compounds in the treatment of human cancer is based on the unique ability of non-radioactive 10B nuclei to absorb thermal (low energy) neutrons. The prompt nuclear reactions which occur on thermal neutron absorption deliver a dose of nearly 2.8 MeV only in the vicinity of boron-containing cells since the nuclear fragments produced (alpha particles and recoil lithium atoms) travel only 10-15 Mum. This technique has become known as boron neutron capture therapy (BCNT), and has been used successfully in Japan to treat brain tumors. As the major plasma cholesterol transport lipoprotein in human plasma, LDL supplies about 90% of the cholesterol needs of living cells. LDL particles are recognized by specific, high-affinity receptors on the exterior cell membrane surface, and are subsequently transported into the cytoplasm by endocytosis. Several types of cancer cells are known to have greatly elevated cholesterol requirements, and this is likely true for most neoplastic cells undergoing rapid growth since cholesterol is a major cell membrane constituent. The native cholesteryl fatty acid ester core of LDL may be removed and replaced with other hydrophobic compounds with no change in physicochemical properties. The compounds chosen for synthesis in this study are carboranes linked covalently to hydrophobic groups such as oleyl, retinyl and cholesteryl. Synthesis and reconstitution studies will be performed at UCSF, while specific uptake of rB-LDL by cultured cells will be examined at Brookhaven National Laboratory through an ongoing collaboration.
| Laster, B H; Kahl, S B; Popenoe, E A et al. (1991) Biological efficacy of boronated low-density lipoprotein for boron neutron capture therapy as measured in cell culture. Cancer Res 51:4588-93 |
