An approach to drug delivery using novel carbohydrates to carry drugs has recently been described in the Proceedings of the National Academy of Sciences. The method exploits the abundance of lectins, or carbohydrate-binding receptors, on the surface of specific cells. The authors demonstrate the delivery of the cancer drug doxorubin targeted to hepatocytes in a mouse liver tumour model.

Known as the LEAPT strategy, lectin-directed enzyme-activated prodrug therapy is a two-stage delivery system. First, a novel non-mammalian glycosidase enzyme, rhamnosidase, is conjugated to a mammalian sugar; this is taken into the target cell by sugar-mediated receptor-mediated endocytosis, via the asialoglycoprotein receptor, a membrane-bound endocytic lectin found in abundance on the surface of hepatocytes in the liver. The second step involves administering the rhamnose-capped pro-drug; the drug is activated in the target cell once the sugar cap is removed by the pre-delivered rhamnosidase enzyme. The rhamnosidase enzyme was isolated from Penicillium decumbens and its carbohydrate structure was specifically engineered through enzymatic de-glycosylation and chemical re-glycosylation with mammalian sugar residues such as mannose and galactose.

Both in vitro and in vivo techniques proved the delivery of rhamnosidase and prodrug to hepatocytes and demonstrated successful activation of the rhamnose-bound prodrug. The authors tested the therapeutic effectiveness of LEAPT by constructing a doxorubicin prodrug, Rha-DOX, and using it in a hepatocellular carcinoma disease mouse model. After 42 days of therapy, the liver tumour burden was shown to have decreased by almost half compared with the control groups receiving either Rha-DOX or glycosylated rhamnosidase alone.

LEAPT achieves higher concentrations of active drug at the target site through the use of engineered glycosylated enzymes than delivery of drug alone. Assuming that suitable receptors can be identified, delivery to other cell types is possible simply by changing the cognate sugar attached to the enzyme. The use of macrophage-associated carbohydrate receptors to treat macrophage-associated diseases such as lysosomal storage diseases or viral infections could benefit from this approach.