Yinping Li, Weiying Hong, Henan Zhang, Tian Tian Zhang, Zhiyong Chen, Shiling Yuan, Peng Peng*, Min Xiao*, Li Xu*

Journal of Controlled Release. 2020, 317, 232-245

Abstract

The success in the application of nanomedicines for tumor therapy is largely dependent on the development of efficient tumor targeting, specific and effective drug delivery systems. Here, through a simple synthetic process, we developed a type of novel glucose transporter 1 (GLUT1)-targeting, tumor microenvironment responsive and near infrared irradiation (NIR) induced cytosolic drug delivery nanoparticles (NPs). Our design was based on polydopamine (PDA) NPs as the photothermal agent and drug delivery carrier, glucosyl functional ligands as the GLUT1 targeting agents, and the conjugation of anticancer drug bortezomib (BTZ) to the catechol groups of PDA NPs in a pH-dependent manner. The in vitro and in vivo studies demonstrated that the functionalized PDA NPs could efficiently accumulate in tumor site and localize in subcellular endo/lysosomes of tumor cells, and they could respond to tumor microenvironment and endo/lysosomal pH as well as NIR to promote the robust release of BTZ. Furthermore, the functionalized PDA NPs were first demonstrated to overcome the endo/lysosomal barrier for the enhanced cytosolic BTZ drug delivery through NIR-triggered endo/lysosomal release, achieving the integration of NIR-triggered photothermal effect and chemotherapy for synergistic tumor ablation. The significant suppression and even complete regression of 4 T1 tumor was observed in mice given only single treatment. Therefore, the GLUT1-targeting, pH and photothermal responsive drug delivery NPs show a great potential for broadly applicable chemo-photothermal tumor therapy.