New cyclodextrin bioconjugates for active tumour targeting

A new cyclodextrin-based carrier for active targeting of low soluble and degradable drugs has been synthesized and characterized. P-Cyclodextrins were first reacted with excess hexamethylene diisocyanate and the resulting CD-(C-6-NCO)(5) derivative was reacted with 700 Da diamino-PEG to yield CD-(C-6-PEG-NH2)(5). About one out of five free amino groups of PEG were functionalised with folic acid (FA) as a tumour targeting moiety. The chemical structures of the intermediates as well as the final product, CD-(C-6-PEG)(5)-FA, were characterized by H-1 and C-13 NMR, reverse phase and gel permeation chromatography, and LW-Vis spectroscopy. After modification, the haemolytic activity of beta-cycloclextrins decreased by about 70%. In the presence of the new carrier, the P-estradiol solubility increased by more than 300 fold and the chlorambucil degradation rate decreased by 50-60%. CD-(C6-PEG)(5)-FA formed an inclusion complex with curcumin displaying an association constant of 954,732 M-1. The new carrier increased the curcumin solubility by about 3200 fold as compared to native P-cyclodextrins and reduced its degradation rate at pH 6.5 and 7.2 by 10 and 45 fold, respectively. FA receptor-overexpressing human nasopharyngeal tumour KB cell lines and non-folic acid receptor-expressing human breast cancer MCF7 cells were used to evaluate the targeting properties of the new drug delivery system. The in vitro studies demonstrate that the new carrier possesses potential selectivity for the folate receptor-overexpressing tumour cells as ED50 values of 52 mu M, 58 mu M and 21 mu M were obtained with curcumin-loaded CD-(C-6-PEG-NH2)(5), curcumin in foetal serum medium and CD-(C-6-PEG)(5)-FA, respectively.