Solid tumors usually present insufficient supply of oxygen

Solid tumors usually present insufficient supply of oxygen, activating the hypoxia inducible factor-1 (HIF-1) pathway, which prompts an adaptive response on genes that regulate glycolytic metabolism, promoting glucose uptake through the transcription of GLUTs [54]. Increasing evidence indicates that such glucose metabolism is even higher in cancer stem-like it is impossible (CSCs), i.e. a sub-population of drug-resistant cancer cells with self-renewal and tumorigenic capabilities, with hypoxic regions in tumors serving as specialized niches for CSC maintenance and GLUT1 having a central role in the stemness, growth and survival of CSCs [[55], [56], [57], [58], [59]]. In fact, GLUT1 expression in tumors has been associated with tumor malignancy and resistance to therapies [16,58], including CDDP resistance in head and neck tumors [23,60,61]. The CSCs in head and neck tumors have been identified as the cellular fraction expressing variant isoforms of CD44 (CD44v), which show high GLUT1 and high cytosolic levels of glutathione that permanently inactivate CDDP [23]. Our previous reports showed that CDDP/m can avoid the glutathione detoxification by increased drug delivery to the nucleus of human oral squamous cell carcinoma HSC-2 cells, which display a large fraction of CD44v-positive CSCs, effectively overcoming drug resistance [62,63]. In current study, we evaluated the antitumor activity against OSC-19 tumors, which have an even larger CD44v-positive sub-population than HSC-2 cells, and are approximately 4-fold more resistant to CDDP than HSC-2 cells [23]. Thus, the activity of CDDP/m was insufficient to suppress the growth of OSC-19 tumors. On the other hand, Gluc-25%-CDDP/m effectively reduced the tumor growth rate, suggesting that the GLUT1-targeting could synergize with the ability of CDDP/m for surmounting drug resistance by increasing the drug levels in tumors, as well as enhancing the activity against GLUT1-expressing cancer cells. Such activity enhancement indicates GLUT1-targeting as an attractive approach for developing therapies against drug resistant tumors.
Conclusion By developing glucose-installed polymeric micelles having the glucose ligands conjugated via the carbon 6 and an engineered ligand density of 25%, we successfully targeted the GLUT1 on the tumor vasculature and on cancer cells, promoting the selective accumulation of the micelles in tumors and enhancing their antitumor activity, even against drug resistant tumors. Targeting the GLUT1 on the tumor vascular endothelium effectively facilitated the translocation of the micelles from the blood compartment into the tumor interstitium, doubling the accumulation levels achieved solely by the EPR effect. Thus, while highly specific markers against tumors are being considered for tumor targeting and emplacement on nanomedicines, which would increase complexity and personalization of therapies due to the heterogeneous nature of cancer, our findings will contribute to drive the development of comprehensive nanomedicine systems capable of targeting tumors through simple glucose biochemistry. Given the glycolytic demands of a wide range of tumors, and its connection with tumor malignancy and drug resistance, our approach has the potential for developing broadly applicable therapeutic strategies against aggressive cancers.
Acknowledgements This research was supported by the Center of Innovation Science and Technology based Radical Innovation and Entrepreneurship Program (COI STREAM; KK) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), the Practical Research for Innovative Cancer Control from Japan Agency for Medical Research and Development (AMED), the Project for Development of Innovative Research on Cancer Therapeutics (P-DIRECT) from AMED. This work was also partially supported by Grants-in-Aid for Scientific Research B (JP16H03179; H.C.) from the Japan Society for the Promotion of Science (JSPS), the Project for Cancer Research And Therapeutic Evolution (P-CREATE) (JP17cm0106202; H.C. and K.K.) from Japan Agency for Medical Research and Development (AMED).