Smart Carbohydrate Nanonets: appealing at the sweet side of cancer

Metastases and the consequences of their treatment are the greatest contributors to death from cancer. [1, 2] The tumor’s aggressiveness is related with accelerated cellular metabolism and therefore an increased glucose uptake.[1, 3] These alterations of the cellular metabolism are considered hallmark of Cancer and therefore important therapeutic target. [4] Among different approaches, biocatalytic self-assembly (BSA) has recently emerged as a selective cancer therapy. It is based on self-assembly process that is triggered by enzyme(s) overexpressed by cancer cells, e.g. alknaline phosphatase (ALP).[5] Until now mainly bioactive peptide analogues functionalized with enzyme-responsive moiety have been used as self-assembling units (gelators) under this approach. These gelators can induce cell death via multiple mechanisms, some of which involve cellular internalization of the gelators with following assembly within the cell. Recently, we suggested an alternative gelator - a simple glucose derivative (N-(fluorenylmethoxycarbonyl)-glucosamine-6-phosphate, Fmoc-GlcN) and demonstrated its potential for treatment of osteosarcoma.[6] We hypothesized that, unlike the peptide amphiphiles used for BSA, the resemblance of Fmoc-GlcN with glucose plays an important role and trigger different apoptotic mechanisms that are the key to selectively inhibit the glycolytic phenotype. Herein, we demonstrate that indeed the aromatic carbohydrate amphiphile differs by the peptides ones. The nanofibers/hydrogel is formed in the pericellular space but not intracellular as observed for peptide amphiphiles. We show that this process is cell specific: apoptosis was induced for osteosarcoma (SaOs2) and hepatocellular carcinoma cells (HepG2) that overexpress membrane-bound ALP while other type of cells (e.g., ATDC5) with low expression of this protein are not affected by the addition of the glucose amphiphile. Possible blocking of glucose transposters (GLUTs) by the used gelator was also studied. We evaluated the expression of several GLUTs in different cell lines. The results suggested that the selective apoptosis is probably induced by two synergistic mechanisms: formation of pericellular net that traps selectively the ALP overexpressing cells and blockage of GLUTs, i.e. the glucose transport, in these cells.