Carboxyl group-terminated polyamidoamine dendrimers bearing glucosides inhibit intestinal hexose transporter-mediated D-glucose uptake.

We are investigating non-absorbable polymeric conjugates bearing glucosides via a omega-amino triethylene glycol linker as oral anti-diabetic drugs that suppress an increase in the blood glucose level after meals through inhibition of Na(+)/glucose cotransporter (SGLT1). When the linker was bound to phloridzin, which is a SGLT1 inhibitor, to yield a precursor of the conjugate, the in vitro inhibitory effect on SGLT1-mediated d-glucose uptake was reduced to about one-tenth that of phloridzin. The inhibitory effect was recovered completely when the precursor was immobilized on the surface of poly(amidoamine) (PAMAM) dendrimers (generation: 3.

Stabilization of enzyme-susceptible glucoside bonds of phloridzin through conjugation with poly(gamma-glutamic acid).

We designed and prepared poly(gamma-glutamic acid)s (gamma-PGA) bearing phloridzin, which is an inhibitor of Na(+)/glucose cotransporter 1 (SGLT1), via a non-biodegradable omega-amino triethylene glycol linker. Properties of gamma-PGA-phloridzin conjugates (PGA-PRZ) were examined because our previous research revealed that PGA-PRZ with a 15% phloridzin content suppressed an increase in the blood glucose level after oral administration of D-glucose in rats, even though intact phloridzin scarcely affected the glucose-induced hyperglycemic effect. In uptake experiments using rat small intestinal brush-border membrane vesicles (BBMVs), the conjugation resulted in a 10-fold increase in the inhibitor concentration giving half-maximum inhibition of SGLT1-mediated D-glucose uptake, indicating that the inhibitory effect on the uptake was considerably reduced.