Liposomal Encapsulation of Sodium Borocaptate and Boronophenylalanine

Liposomes have been extensively evaluated as nanovehicles for the delivery of boron compounds for NCT.99,100 In vitro and in vivo studies have demonstrated that they can effectively and selectively deliver large quantities of boron to tumors and that the compounds delivered by liposomes have a longer tumor retention time. BPA is an amino acid analogue that is preferentially taken up by cells with increased metabolic activity, such as tumor cells of varying histopathologic types

Bilayer memberane

Internal aqueous space

FIGURE 6.6 Schematic diagram of the structure of a liposome that has an aqueous core and a lipid bilayer membrane. The latter is composed of polar head groups with hydrocarbon tails. The liposomal surface can be modified by PEGylation to prolong its circulation time and linked to either a mAb or a ligand for targeting.

Hydrocarbon tails t I

\ / Polar head groups mAb or ligand = PEG

Bilayer memberane

Internal aqueous space

FIGURE 6.6 Schematic diagram of the structure of a liposome that has an aqueous core and a lipid bilayer membrane. The latter is composed of polar head groups with hydrocarbon tails. The liposomal surface can be modified by PEGylation to prolong its circulation time and linked to either a mAb or a ligand for targeting.

including melanomas,31,101 gliomas102, and squamous cell carcinomas.103,104 Because of its low aqueous solubility, BPA has been used as a fructose complex, which has permitted it to be administered i.v. rather than orally.105,106 Following i.v. administration of BPA, which had been incorporated into conventional liposomes, there was rapid elimination by the RES with very low blood boron concentrations at 3 h. In contrast, if BPA was incorporated into liposomes composed of distearoyl phosphoethanolamine (DSPE)-PEG, therapeutically effective tumor boron concentrations (greater than 20 mg/g) were seen at 3 h and at 6 h, indicating that PEG-liposomes had evaded the RES.107 In addition, BPA has been incorporated into the lipid bilayer of liposomes, composed of positively charged lipid 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) and the zwitterionic lipid, 1,2-dioleoyl-sn-glycerol-3-phosphoethanolamine (DOPE).108 Cationic liposomes have been widely used as carriers of biomolecules that specifically target the cell nucleus,109 which would be advantageous for BNCT. Another clinically used drug, BSH, has been incorporated into liposomes composed of dipalmitoylphosphatidylcholine (DPPC)/Chol in a 1:1 molar ratio with and without PEG stabilization.110 The average diameter of liposomes containing BSH was in the range of 100-110 nm. Both types of liposomes resulted in a significant improvement in their circulation time compared to that of free BSH. At 24 h following i.v. injection of PEG-liposomes, 19% of the I.D. of boron was in the blood compared to 7% following formulation of BSH in conventional liposomes. The mean percent uptake by the liver and spleen was not significantly different for the two types of liposomes. However, the blood to RES ratios were higher for PEG-liposomes at all time points indicating that a higher fraction of the injected dose (I.D.) of BSH was still in the blood. Ji et al. have reported that there were no significant differences in the in vitro uptake by 9L gliosarcoma cells of free BSH versus a liposomal formulation after 16 h incubation. However, cellular persistence was increased at 12 and 24 h for BSH-loaded liposomes.111 BSH also has been incorporated into transferrin (TF) conjugated PEG liposomes (TF-PEG liposomes),112 which then were taken up by cells via TF receptor-mediated endocytosis. Intravenous administration of this formulation increased boron retention at the tumor site compared with PEG liposomes, bare liposomes or free BSH and suppressed tumor growth following BNCT. These results suggest that TF targeted liposomes might be useful as intracellular targeting vehicles.

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