Targeted Norcantharidin Delivery Based On Charge-Reversal Concept

Amides with β-carboxylic acid groups are stable and negatively charged at physiological pH, thus are less toxic to the body. They can hydrolyze and regenerate the corresponding amines and anhydrides (or diacids) once in acidic environments. Using this reaction a charge-reversal concept has been developed for nuclear drug delivery.We proposed to use this charge reversal concept to targeted deliver an anhydride-structured antitumor drug norcantharidin (NCTD). NCTD can be reacted with the cationic polymer to form β-carboxylic amides. NCTD acts as an anhydride that amidizes the amines to form the acid-labile amides, and it is an antitumor drug as well.In this thesis, branched PEI (BPEI), linear PEI (LPEI), PLL and PAMAM are used as cationic carriers, and reacted with NCTD to form acid-labile β-carboxylic amides. The amides are stable and negatively charged at the physiological pH, but they hydrolyze and regenerate the NCTD and the amine groups carrying cationic charges in acidic lysosomes. The regerenated cationic polymers lyze the lysosomes and release the drug into cytoplasm. Folic acid (FA) moieties are introduced to the charge reversal carrier for active targeting. The results indicate that the FA moieties can significantly enhance the cellular uptake of the carrier, for instance, the cellular uptake of FPLL-NCTD to BCap37cells was95%after incubated for3h. In addition, the FA targeting conjugates FPEI-NCTD and FPLL-NCTD have much higher cytotoxicity than the PEI-NCTD and PLL-NCTD conjugates. The IC50of the former two conjugates is only1/25of those from the latters conjugates, indicating that the FA moieties can greatly enhance the anticancer efficiency of the charge-reversal conjugates.