Maltoheptaose-Presenting Nanoscale Glycoliposomes for the Delivery of Rifampicin to E. coli

Liposomes, a nanoscale drug delivery system, are well known for their ability to improve pharmacokinetics and reduce drug toxicity. In this work, maltoheptaose (G7)-presenting glycoliposomes were synthesized and evaluated in the delivery of the antibiotic rifampicin. Two types of liposomes were prepared: nonfluid liposomes from L-alpha-phosphatidylcholine ( PC) and cholesterol, and fluid liposomes from 1,2-dipalmitoyl-sn-glycero-3-phosphocholine and 1,2-dimyristoyl-sn-glycero-3-phospho-(1'rac-glycerol). G7-derivatized glycolipid, G7-DPPE (DPPE: 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine), was incorporated into the liposomes at 21 and 14 mu mol/mg to form nanoparticles of 75 +/- 12 and 146 +/- 14 nm for the nonfluid and fluid G7-glycoliposomes, respectively. The multivalent G7-glycoliposomes were characterized by lectin binding with concanavalin A (Con A). The dissociation constant Kd between Con A and the nonfluid or fluid G7-glycoliposomes was 0.93 or 0.51 mu M, which represented similar to 900- or 1600-fold stronger affinity than the binding between Con A and G7. The G7-glycoliposomes were loaded with rifampicin at 6.6 and 16 wt % encapsulation for the nonfluid and fluid G7glycoliposomes, respectively. Introducing a carbohydrate in the liposomes slowed down the release of rifampicin, with the G7glycoliposomes having the slowest release rate and the lowest permeability coefficient among the liposome formulations. The fluid G7-glycoliposomes lowered the minimal inhibitory concentration (MIC) of rifampicin against E. coli ORN208 by about 3 times, whereas liposomes without G7 or Man (D-mannose)-glycoliposomes showed no improvement in MIC. The rifampicin-loaded fluid G7-glycoliposomes demonstrated the best sustained antibacterial activity against E. coli, with up to 2 log reduction in the colony forming units at 4 x MIC after 24 h. Fluorescence resonance energy transfer and confocal fluorescence microscopy revealed stronger interactions of the bacterium with the fluid G7-glycoliposomes than other liposome formulations.

Automated summary

Liposomes, especially G7-glycoliposomes, loaded with rifampicin showed improved antibacterial activity, with fluid G7-glycoliposomes exhibiting the best sustained activity against E. coli. Introduction of carbohydrates in the liposomes slowed down the release of rifampicin, leading to a lower permeability coefficient. The multivalent G7-glycoliposomes had significantly stronger affinity towards Con A compared to the binding between Con A and G7.