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  • Here we studied GLUT targeted nanomedicines as a new strateg


    Here, we studied GLUT1-targeted nanomedicines as a new strategy directed to overcome vascular barrier, enhancing delivery and efficacy in solid tumors. These nanomedicines were prepared by controlled installation of glucose on polymeric micelles incorporating the antitumor agent cisplatin, which is used for the treatment of a wide range of tumors (Fig. 1). The cisplatin-loaded micelles (CDDP/m) serving as the platform for this study have shown potent antitumor effects and reduced side effects in humans, and are being evaluated in Phase III clinical trials against pancreatic cancer [7,22]. Before evaluating the effects of GLUT1-targeting on these micelles, the expression of GLUT1 on the endothelial AH 7614 of tumor blood vessels was validated in xenografts and clinical tumor biopsies. Then, the ability of glucose-installed CDDP/m (Gluc-CDDP/m) to improve delivery efficiency through the glucose/GLUT1 system was compared in vitro, as well as in vivo against two tumor models, i.e. the high-GLUT1-expressing human squamous cell carcinoma of the head and neck (OSC-19), which harbor a large subpopulation of cisplatin-resistant cells with cancer stem-like cell characteristics [23], and the low-GLUT1-expressing human glioblastoma-astrocytoma (U87MG) [24]. Our results demonstrated that precisely tuning the micelles to have 25% of their PEG chains with glucose conjugated at the carbon 6 via ether linkage promoted the selective accumulation in the tumors through GLUT1-associated vascular translocation. The intratumoral levels of these micelles in both GLUT1-high OSC-19 and GLUT1-low U87-MG tumors were 2-fold higher than those of the control CDDP/m in these tumors, which are solely based on the EPR effect, allowing Gluc-CDDP/m to improve the antitumor activity. These findings indicate our approach of exploiting the GLUT1/glucose interaction by glucose-installed nanomedicines as a promising new strategy for boosting delivery and efficacy of nanomedicines against solid tumors.
    Materials and methods
    Discussion The surface density of ligands is a critical parameter for adjusting the binding affinity of nanoparticle-based systems, as the increased number of ligands will prompt stronger multivalent interactions with the targets on the cells. Here, we used Gluc-25%- and Gluc-50%-CDDP/m, and observed that having a glucose density of 50% on the micelles neither improved the in vitro efficacy in OSC-19 spheroids, nor enhanced the drug levels in the tumors in vivo, indicating the importance of engineering the density of glucose moieties on the micelles. Moreover, Gluc-50%-CDDP/m showed higher accumulation than Gluc-25%-CDDP/m in liver. Such differences between Gluc-25%-CDDP/m and Gluc-50%-CDDP/m could be associated with a tighter multivalent binding of the Gluc-50%-CDDP/m to a number of GLUT1 molecules expressing on the cellular surface compared to Gluc-25%-CDDP/m, which may facilitate the retention of the former in liver and reduce the transvascular transport of Gluc-50%-CDDP/m into tumors. We have previously studied such multivalency effect by surface plasmon resonance using lactose-installed polymeric micelles [39]. This study confirmed that the multivalent binding of the micelles accelerated the association phase and slowed the dissociation phases. Moreover, the multivalent bonding has been previously observed for a wide range of nanoparticles and supramolecular systems modified with ligands, such as cRGD peptide [[40], [41], [42]]. In fact, we previously observed a comparable effect of cRGD ligands on nanocarriers, where the strong integrin binding at high ligand densities promoted the retention in liver and impaired the extravasation in tumors [42]. In addition, while the effect of modifying the micelles with glucose densities between the 25–50% range has not been explored, it is likely that there is an optimal glucose density for selectively increasing the accumulation in the tumor, while overcoming the liver barrier. While such optimization is beyond the scope of this study, our conclusion that the density of glucose should be carefully engineered to promote tumor accumulation and avoid the sequestration in the organs is supported by the findings with 0%, 25% and 50% glucose densities.