Overcoming the Heat Endurance of Tumor Cells by Interfering with the Anaerobic Glycolysis Metabolism for Improved Photothermal Therapy

Abstract

In this study, we developed a general method to decorate plasmonic gold nanorods (GNRs) with a CD44-targeting functional polymer, containing a hyaluronic acid (HA)-targeting moiety and a small molecule Glut1 inhibitor of diclofenac (DC), to obtain GNR/HA-DC. This nanosystem exhibited the superiority of selectively sensitizing tumor cells for photothermal therapy (PTT) by inhibiting anaerobic glycolysis. Upon specifically targeting CD44, sequentially time-dependent DC release could be achieved by the trigger of hyaluronidase (HAase), which abundantly existed in tumor tissues. The released DC depleted the Glut1 level in tumor cells and induced a cascade effect on cellular metabolism by inhibiting glucose uptake, blocking glycolysis, decreasing ATP levels, hampering heat shock protein (HSP) expression, and ultimately leaving malignant cells out from the protection of HSPs to stress (e.g., heat), and then tumor cells were more easy to kill. Owing to the sensitization effect of GNR/HA-DC, CD44 overexpressed tumor cells could be significantly damaged by PTT with an enhanced therapeutic efficiency in vitro and in vivo.

Nanoparticle‐based photothermal and photodynamic immunotherapy for tumor treatment

“…In terms of tumor therapy, to the best of our knowledge, PTT exerts antitumor effects mainly through direct thermal ablation (over 42 C). 31 33 Ali et al used quercetin, a HSP70 siRNA and HSP70 inhibitor, to enhance gold-nanorod-based PTT and achieved satisfactory results, that is, a potent cytotoxic effect on a wide range of tumor tissues at low laser power. [23][24][25] Therefore, tumor ablation can be improved by increasing the hyperthermia temperature, which researchers typically achieve by increasing the power of irradiation light or the concentration of photothermal agents.…”

“…However, excessive laser power or agent dose causes safety risks to nonneoplastic tissues. 31 The antitumor effects of PTT include not only hyperthermia-caused cell apoptosis and necrosis but also other potential effects (Fig. For example, mitochondria-targeting nanoparticles can elevate the level of intracellular reactive oxygen species (ROS) after PTT with substantially reducing the NIR power density, causing a mitochondrial dysfunction and triggering apoptosis.…”

“…Therefore, antagonizing HSPs, such as HSP70 and HSP90, which are strongly associated with heat resistance, may improve the efficacy of PTT. 31 RNA interference or HSP inhibitors are generally selected. Yang et al synthesized PEG modified 1D polymer nanofibers loaded with gambogic acid, a potent inhibitor of HSP90, to effectively downregulate hyperthermia-induced HSP90 and thus overcome the heat resistance of tumor cells in PTT.…”

“…The glucose transporter 1 inhibitor inhibits glucose transport, thereby blocking glycolysis, reducing ATP synthesis and ultimately reducing the expression level of HSPs (not a single kind but all). 31 The antitumor effects of PTT include not only hyperthermia-caused cell apoptosis and necrosis but also other potential effects ( Fig. 1).…”

A DNA–Azobenzene Nanopump Fueled by Upconversion Luminescence for Controllable Intracellular Drug Release

“…Thec ontinuous rotation-inversion movement of the phenyl moiety of azo in the hybridization zone of DNA backbones (DNAs trands LA Azo ,L C Azo with 3azo moieties per DNAstrand) determined the feasibility of the molecular impeller pump via DNAhybridization [13] and dehybridization to controllably release DOX upon NIR irradiation.To diminish the active efflux of adrug by transporters like P-glycoprotein (P-gp) on cell membrane, [14] HIV-1 TAT, an uclear localization peptide, [15] was conjugated to the DNA-azo nanopump for nuclear targeting (Scheme 1b), which greatly enhanced the concentration of DOXinnuclear area, and thus improved therapeutic efficacy. Considering the need for cancer-cell targeting,a nionic hyaluronic acid (HA) was also coated on the nanopump via electrostatic adsorption to specifically recognize CD44-overexpressing tumor cells to trigger HA-mediated endocytosis, [17] while hyaluronidase (HAase) in the tumor microenvironment [16] hydrolyzes HA to expose TATf or nuclear targeting (Scheme 1c). The presence of HA coating prevented nonspecific interaction with serum components during delivery process, [18] and prevented the off-target effect.…”