Abstract
Specific link between high fructose uptake and cancer development and progression highlighted fructose transporters as potential means to achieve GLUT-mediated discrimination between normal and cancer cells. The gained expression of fructose-specific transporter GLUT5 in various cancers offers a possibility for developing cancer-specific imaging and bioactive agents. Herein, we explore the feasibility of delivering a bioactive agent through cancer-relevant fructose-specific transporter GLUT5. We employed specific targeting of GLUT5 by 2,5-anhydro-D-mannitol and investigated several drug conjugates for their ability to induce cancer-specific cytotoxicity. The proof-of-concept analysis was carried out for conjugates of chlorambucil (CLB) in GLUT5-positive breast cancer cells and normal breast cells. The cytotoxicity of conjugates was assessed over 24 h and 48 h, and significant dependence between cancer-selectivity and conjugate size was observed. The differences were found to relate to the loss of GLUT5-mediated uptake upon increased conjugate size and hydrophobicity. The findings provide information on the substrate tolerance of GLUT5 and highlight the importance of maintaining appropriate hydrophilicity for GLUT-mediated delivery.
Highlights
The development of targeted approaches is the ultimate goal to achieve improvements in disease diagnostics and treatment
While GLUTs have been viewed as important therapeutic targets for several decades, as yet the progress of specific targeting of GLUTs for drug delivery is minimal [16]
Using GLUT5-directing 2,5-anhydro-D-mannitol, we have aimed to explore the feasibility of delivering a bioactive cargo through GLUT5 and achieving cancer specificity of the cytotoxic response
Summary
The development of targeted approaches is the ultimate goal to achieve improvements in disease diagnostics and treatment. As a consequence of enhanced energy requirements, higher sugar concentrations are needed for anabolic reactions to continue replication. Higher sugar uptake in cancers is reflected by the elevated activity and gained expression of facilitative sugar transporters—GLUTs. GLUTs are not coupled with energy, and sugar translocation across the cell membrane occurs via gradient-dependent influx and efflux of carbohydrates [4]. Individual GLUT isoforms demonstrate different tissue specificity, substrate specificity, and kinetic characteristics. Glucose is the predominant one among various carbohydrates that are transported by GLUTs. In addition to glucose, GLUTs supply cells with galactose, fructose, and other sugars. The transport kinetics and affinity for sugars differ between GLUTs, with the majority taking up more than one substrate and selected few showing substrate specificities [5,6]
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