In tumor cells, glutamine is progressively consumed along metabolic pathway for tumor growth and survival. To this end, tumor cells overexpress glutamine transporters, compared to normal cells, and this aggressive demand of glutamine in tumor cells potentially leads to crafting a glutamine-based drug with tumor specificity. In this regard, it is conjectured that the multivalent glutamine moieties in a molecule would enhance the interaction with tumor cells as well as tumor selectivity. Thus, in order to evaluate the glutamine-based multivalent interaction with tumor cells, we developed polymeric molecules with different degrees of polymerization (DPs) having glutamine pendant groups in the side chains (Figure 1a). In synthesis, the side chains of poly(lysine) (P(Lys)) with azide terminus (DP = 25, 50, and 100) were modified to bear glutamine moiety (P[Lys(Gln)]), and control polymer was also prepared via α-carboxyl amide formation (P[Lys(α-Glu)]) for confirming the requirement of glutamine structure toward tumor specificity (Figure 1b). In addition, the azide terminus of the polymers was reacted with Cy5-cyclooctine for fluorescent detection in the following experiments. The treatment with the polymers for cultured BxPC3 cells (human pancreatic cancer cells) resulted in increased Cy5 fluorescence intensity for the cells treated with P[Lys(Gln)] in a DP-dependent manner. This result suggests that the multivalency of glutamine moieties in one molecule facilitates cellular uptake possibly due to the multivalent interaction of the polymer with tumor cells. Of note, the fluorescence intensity of the cells treated with P[Lys(α-Glu)] was significantly lower than the cells treated with P[Lys(Gln)], confirming the requirement of glutamine moieties for facilitated uptake in tumor cells. Altogether, we successfully demonstrated that multivalency of glutamine moieties in one molecule can facilitate uptake in tumor cells, and the obtained result would generate a new strategy for the development of tumor-specific drug.

Novel design of glutamine-derived polymer with a high affinity to cancer cells based on aberrant glutamine metabolism

253rd National Meeting (2017)

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