Objectives: We have previously demonstrated that radiolabeled-monomeric glucosamine conjugates selectively target GLUT transporters.1 The purpose of this study was: (1) to evaluate GLUT targeting specificity of dimeric bioconjugate, RMX-GC2; (2) to determine the effect of the dimeric structure on accumulation of agent in breast cancer, prostate cancer and metastatic melanoma cells compared to its monomeric analogs. Methods: The monovalent glucosamine conjugates RMX-GC were synthesized by Cu-free click chemistry; the dimeric conjugate RMX-GC2 was synthesized using a scaffold of branched PEG and AEEA-glucosamine as building block. The Cu64/Pb203-radiolabeling of agents were carried out under mild conditions in 0.5M NH4OAc (pH 5.5). The GLUT1 binding properties of agents were determined by cellular uptake in mutiple cancer cell lines. GLUT-specificity was confirmed by co-incubation of the agents with known GLUT-specific ligands (phloretin; cytochalasin B; glucosamine) in cancer cell lines. Results: Radiolabeling of agents were completed under mild conditions (15min/37oC). The dimeric RMX-GC2 demonstrated high retention in cancer cell lines with almost 2x-fold higher accumulation in tested melanoma cancer cell lines B16(F10) (35.1 %ID/mg) compared to A375 (18.2 %ID/mg). The co-incubation of the radiolabeled RMX-GC2 with GLUT specific ligands (cytochalasin B) reduced its uptake by 91% in A375 cells and 87.5% in B16(F10) cells. In independent in vitro studies, uptake of monovalent RMX-AEEA-GC was 3x-fold lower (&lt;5.5% ID/mg) than the RMX-GC2 under identical experimental conditions. Conclusion: Our feasibility studies confirmed the synergistic effect of dimeric structure of RMX-GC2 on its increased GLUT targeting properties/specificity compared to monomeric analog in tested cancer cell lines. 1.2011 I.Tworowska et al, US granted patent WO2012177701-A2.

Multivalent glucosamine conjugates for targeted image-guided therapy of cancer

254th National Meeting (2017)

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