Glucose transporter 1-mediated vascular translocation of nanomedicines enhances accumulation and efficacy in solid tumors

Kazumi Suzuki, Yutaka Miura, Yuki Mochida, Takuya Miyazaki, Kazuko Toh, Yasutaka Anraku, Vinicio Melo, Xueying Liu, Takehiko Ishii, Osamu Nagano, Hideyuki Saya, Horacio Cabral, Kazunori Kataoka

研究成果: Article

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抜粋

Nanomedicine modification with ligands directed to receptors on tumor blood vessels has the potential for selectively enhancing nanomedicine accumulation in malignant tissues by overcoming the vascular barrier of tumors. Nevertheless, the development of broadly applicable ligand approaches capable of promoting the transvascular transport of nanomedicines in a wide spectrum of tumors has been elusive so far. By considering the indispensable and persistent glycolytic fueling of tumors, we developed glucose-installed polymeric micelles loading cisplatin (Gluc-CDDP/m) targeting the glucose transporter 1 (GLUT1), which is overexpressed in most tumors and present on vascular endothelial cells, toward improving the delivery efficiency and therapeutic efficacy. The design of the glucose ligands on Gluc-CDDP/m was engineered to control the conjugation via the carbon 6 of the glucose moieties, as well as the ligand density on the poly (ethylene glycol) (PEG) shell of the micelles. The series of micelles was then studied in vitro and in vivo against GLUT1-high human squamous cell carcinoma of the head and neck OSC-19 cells and GLUT1-low human glioblastoma-astrocytoma U87MG cells. Our results showed that precisely tuning the micelles to have glucose ligands on 25% of their PEG chains increased the efficacy against the tumors by significantly enhancing the tumor accumulation, even in GLUT1-low U87MG tumors. The enhancement of the intratumoral levels of these micelles was hindered by concomitant administration of glucose, or the GLUT1 inhibitor STF-31, confirming a GLUT1/glucose-mediated increment of the accumulation. Intravital confocal laser scanning microscopy imaging of tumor tissues further demonstrated the rapid extravasation and penetration of Gluc-CDDP/m in OSC-19 tumors compared to non-targeted CDDP/m. These findings indicate GLUT1-targeting as a promising approach for overcoming the vascular barrier and boosting the delivery of nanomedicine in tumors.

元の言語English
ページ(範囲)28-41
ページ数14
ジャーナルJournal of Controlled Release
301
DOI
出版物ステータスPublished - 2019 5 10

ASJC Scopus subject areas

  • Pharmaceutical Science

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    Suzuki, K., Miura, Y., Mochida, Y., Miyazaki, T., Toh, K., Anraku, Y., Melo, V., Liu, X., Ishii, T., Nagano, O., Saya, H., Cabral, H., & Kataoka, K. (2019). Glucose transporter 1-mediated vascular translocation of nanomedicines enhances accumulation and efficacy in solid tumors. Journal of Controlled Release, 301, 28-41. https://doi.org/10.1016/j.jconrel.2019.02.021