Boron Delivery By Dextrans

Dextrans are glucose polymers that consist mainly of a linear a-1,6-glucosidic linkage with some degree of branching via a 1,3-linkage.142,143 Dextrans have been used extensively as drug and protein carriers to increase drug circulation time.144,145 In addition, native or chemically-modified dextrans have been used for passive targeting to tumors, the RES or active receptor-specific cellular targeting. To link boron compounds to dextrans,146 b-decachloro-o-carborane derivatives, in which one of the carbon atoms was substituted by -CH2CHOHCH2-O-CH2CH=CH2, were epoxidized and then subsequently bound to dextran with a resulting boron content of 4.3% (w/w).147 The modified dextran then could be attached to tumor-specific antibodies.147-150 BSH was covalently coupled to dextran derivatives by two methods.151 In the first method, dextran was activated with 1-cyano-4-(dimethylamino)pyridine (CDAP) and subsequently coupled with 2-aminoethyl pyridyl disulfide. Then, thiolated dextran was linked to BSH in a disulfide exchange reaction. A total of 1020 boron cages were attached to each dextran chain. In the second method, dextran was derivatized to a multiallyl derivative (Figure 6.10, 17), which was reacted with BSH in a free-radical-initiated addition reaction. Using this method, 100-125 boron cages could be attached per dextran chain, suggesting that this derivative might be a promising template for the development of other HMW delivery agents. In the second method, designed to target EGFR overexpressing cells, EGF and BSH were covalently linked to a 70 kDa dextran (18).152-154 Bioconjugates, having a small number of BSH molecules, attained maximum in vitro binding at 4 h with the human glioma cell line U-343

FIGURE 6.10 Preparation of EGF-targeted, boronated dextrans. The bioconjugate was prepared by a free-radical-initiated addition reaction between multiallyl dextran derivatives and BSH or thiolated EGF at 50°C using K2S2O8 as an initiator.

MGaC12:6. In contrast, there was a slow increase of binding over 24 h for those having a large number of BSH molecules. Although most of the bioconjugates were internalized, in vitro retention was low, as was in vivo uptake following i.v. injection into nude mice bearing s.c. implants of Chinese hamster ovary (CHO) cells transfected with the human gene encoding EGFR (designated CHO-EGFR). However, following i.t. injection, boron uptake was higher with CHO-EGFR(C) tumors compared to wildtype EGFR( —) CHO tumors.155

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