Involvement of functional groups on the surface of carboxyl group-terminated polyamidoamine dendrimers bearing arbutin in inhibition of Na⁺/glucose cotransporter 1 (SGLT1)-mediated D-glucose uptake.

A carboxyl group-terminated polyamidoamine dendrimer (generation: 3.0) bearing arbutin, which is a substrate of Na⁺/glucose cotransporter 1 (SGLT1), via a nonbiodegradable ω-amino triethylene glycol linker (PAMAM-ARB), inhibits SGLT1-mediated D-glucose uptake, as does phloridzin, which is a typical SGLT1 inhibitor. Here, since our previous research revealed that the activity of arbutin was dramatically improved through conjugation with the dendrimer, we examined the involvement of functional groups on the dendrimer surface in inhibition of SGLT1-mediated D-glucose uptake. PAMAM-ARB, with a 6.25% arbutin content, inhibited in vitro D-glucose uptake most strongly; the inhibitory effect decreased as the arbutin content increased. In vitro experiments using arbutin-free original dendrimers indicated that dendrimer-derived carboxyl groups actively participated in SGLT1 inhibition. However, the inhibitory effect was much less than that of PAMAM-ARB and was equal to that of glucose moiety-free PAMAM-ARB. Data supported that the glucose moiety of arbutin was essential for the high activity of PAMAM-ARB in SGLT1 inhibition. Analysis of the balance of each domain further suggested that carboxyl groups anchored PAMAM-ARB to SGLT1, and the subsequent binding of arbutin-derived glucose moieties to the target sites on SGLT1 resulted in strong inhibition of SGLT1-mediated D-glucose uptake.

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: 3.0) by coupling with one-eighth or less of the terminal carboxyl groups. We considered that the phloridzin-derived glucose moiety on the dendrimer surface was prerequisite for SGLT1 inhibition but that the aglycon part was not always required for the inhibition. Commercially used arbutin, a SGLT1 substrate, was substituted for phloridzin whose aglycon is composed of toxic phloretin. The in vitro inhibitory effect of arbutin was about one-thirtieth that of intact phloridzin; however, the inhibitory effect of the PAMAM dendrimer-arbutin conjugates was as strong as that of the PAMAM dendrimer-phloridzin conjugates. Rat experiments further showed that the PAMAM dendrimer-arbutin conjugates significantly suppressed d-glucose-induced hyperglycemic effects. The dendritic conjugate bearing arbutin appears to be a good candidate as an oral anti-diabetic drug.