ABSTRACT
Ferroptosis, a newly discovered form of regulated cell death, is emerging as a promising approach to tumor therapy. However, the spatiotemporal control of cell-intrinsic Fenton chemistry to modulate tumor ferroptosis remains challenging. Here, we report an oxazine-based activatable molecular assembly (PTO-Biotin Nps), which is capable of triggering the lysosomal dysfunction-mediated Fenton pathway with excellent spatiotemporal resolution via near-infrared (NIR) light to evoke ferroptosis. In this system, a pH-responsive NIR photothermal oxazine molecule was designed and functionalized with a tumor-targeting hydrophilic biotin-poly(ethylene glycol) (PEG) chain to engineer well-defined nanostructured assemblies within a single-molecular framework. PTO-Biotin Nps possesses a selective tropism to lysosome accumulation inside tumor cells, accommodated by its enhanced photothermal activity in the acidic microenvironment. Upon NIR light activation, PTO-Biotin Nps promoted lysosomal dysfunction and induced cytosolic acidification and impaired autophagy. More importantly, photoactivation-mediated lysosomal dysfunction via PTO-Biotin Nps was found to markedly enhance cellular Fenton reactions and evoke ferroptosis, thereby improving antitumor efficacy and mitigating systemic side effects. Overall, our study demonstrates that the molecular engineering approach of pH-responsive photothermal oxazine assemblies enables the spatiotemporal modulation of the intrinsic ferroptosis mechanism, offering a novel strategy for the development of metal-free Fenton inducers in antitumor therapy.
Subject(s)
Ferroptosis , Nanoparticles , Neoplasms , Humans , Doxorubicin/chemistry , Biotin , Neoplasms/drug therapy , Lysosomes , Hydrogen-Ion Concentration , Cell Line, Tumor , Nanoparticles/chemistry , Tumor MicroenvironmentABSTRACT
Herein, a novel two-photon ratiometric fluorescence assay was proposed for monitoring endogenous steroid sulfatase (STS) activity, which could be applied for the ratiometric imaging of STS activity in the endoplasmic reticulum of living cells and tissues and also could be used to distinguish estrogen-dependent tumor cells from other types of cells.
Subject(s)
Fluorescent Dyes/chemistry , Naphthalimides/chemistry , Steryl-Sulfatase/analysis , Animals , Cell Line, Tumor , Endoplasmic Reticulum/metabolism , Fluorescent Dyes/metabolism , Fluorescent Dyes/toxicity , HEK293 Cells , Helix, Snails/enzymology , Humans , Limit of Detection , Microscopy, Fluorescence/methods , Molecular Docking Simulation , Naphthalimides/metabolism , Naphthalimides/toxicity , Photons , Protein Binding , Steryl-Sulfatase/metabolismABSTRACT
Hydrogen polysulfides (H2S n , n > 1) have continuously been proved to act as important signal mediators in many physiological processes. However, the physiological role of H2S n and their signaling pathways in complex diseases, such as the most common liver disease, nonalcoholic fatty liver disease (NAFLD), have not been elucidated due to lack of suitable tools for selective detection of intracellular H2S n . Herein, we adopted a general and practical strategy including recognition site screening, construction of a ratiometric probe and self-assembly of nanoparticles, to significantly improve the probes' selectivity, photostability and biocompatibility. The ratiometric probe PPG-Np-RhPhCO selectively responds to H2S n , avoiding interaction with biothiol and persulfide. Moreover, this probe was applied to image H2S n in NAFLD for the first time and reveal the H2S n generation pathways in the cell model of drug-treated NAFLD. The pathway of H2S n revealed by PPG-Np-RhPhCO provides significant insights into the roles of H2S n in NAFLD and future drug development.
ABSTRACT
Development of a facile but high-efficient small organic molecule-based photothermal therapy (PTT) in the in vivo transparent window (800-900 nm) has been regarded as a minimally invasive and most promising strategy for potential clinical cancer treatment. Phthalocyanine (Pc) molecules with remarkable photophysical and photochemical properties as well as high extinction coefficients in the near-infrared region are highly desirable for PTT, but as far satisfying single-component Pc-based PTT within the in vivo transparent window (800-900 nm) has very rarely been reported. Herein, inspired by the self-assembly algorithm of natural bacteriochlorophylls c, d, and e, biomimetic self-assembling tetrahexanoyl Pc Bio-ZnPc with outstanding light-harvesting capacity was demonstrated to exhibit excellent PTT efficacy evidenced by both in vitro and in vivo results, within the biological transparent window.
