Folate Receptor Targeted Liposomes

A highly ionized boron compound, Na3B20H17NH3, was incorporated into liposomes by passive

131 137 138

loading.131,137,138 This showed high in vitro uptake by the FR expressing human cell line KB (American Type Culture Collection CCL 17), which originally was thought to be derived from a squamous cell carcinoma of the mouth, and subsequently was shown to be identical to HeLa cells, as determined by isoenyzyme markers, DNA fingerprinting, and karyotypic analysis. KB tumor-bearing mice that received either FR-targeted or nontargeted control liposomes had equivalent tumor boron values (approximately 85 mg/g), which attained a maximum at 24 h, while the T:Bl ratio reached a maximum at 72 h. Additional studies were carried out with the lipophilic boron compound, K[n/do-7-CH3(CH2)15-7,8-C2B9Hn. This was incorporated into large unilamellar vesicles, approximately 200 nm in diameter, which were composed of egg PC/Chol/K[mdo-7-CH3(CH2)15-7,8-C2B9Hn] at a 2:2:1, mol/mol ratio, and an additional 0.5 mol% of folate-PEG-DSPE or PEG-DSPE for the FR-targeted or nontargeted liposomal formulations.139 The boron uptake by FR-overexpressing KB cells, treated with these targeted liposomes, was approximately 10 times greater compared with those treated with control liposomes. In addition, BSH and

FIGURE 6.9 Structures of five weakly basic boronated polyamines encapsulated in FR-targeting liposomes. Two spermidine (12, 13) and three spermine derivatives (14—16) that contain hydrophilic amine groups and lipophilic carboranyl cages had DNA-binding properties.

five weakly basic boronated polyamines were evaluated (Figure 6.9). Two of these were the spermidine derivatives N5-(4-carboranylbutyl)spermidine • 3HCl (12) and N5-[4-(2-aminoethyl-o-carboranyl)butyl] spermidine 4HCl (13). Three were the spermine derivatives N5-(4-o-carboranyl-butyl) spermine • 4HCl (14), N5-[4- (2-aminoethyl -o-carboranyl) butyl] spermine 5HCl (15), and N5,N10-bis(4 -o-carboranylbutyl) spermine • 4HCl (16). These were incorporated into liposomes by a pH-gradient-driven remote loading method with varying loading efficiencies that were influenced by the specific trapping agent and the structure of the boron compound. Greater loading efficiencies were obtained with lower molecular-weight boron derivatives, using ammonium sulfate as the trapping agent, compared to those obtained with sodium citrate.

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