Design of multifunctional theranostic nanoplatforms with glutathione-triggered H2S generation and H2S-activitated multi-modal therapy

Hydrogen sulfide (H2S) is a specific substance in the tumor microenvironment, and highly expressed H2S can be used to activate some agents for intelligent treatment of tumors. However, not all tumors contain overexpressed hydrogen sulfide. To address this obstacle, we report the design of theranostic nanoplatforms with glutathione-triggered H2S generation and H2S-triggered therapy activation functions, by using hollow mesoporous organosilica nanoparticles (HMON) to load Cu-HMME framework nanodots (CuHF) and garlic extract diallyl trisulfide (DATS). Such CuHF/DATS@HMON with sizes of about 110 nm exhibit obvious quenching fluorescence and is inactive. Importantly, when CuHF/DATS@HMON is mixed with glutathione (GSH) solution, the nucleophilic attack of GSH on trisulfide bonds (−S-S-S-) in DATS generates S-allyl glutathione disulfide (GSSA) and allyl perthiol (ASSH), with the latter releasing H2S upon reduction by GSH, conferring the overexpress of H2S as the first-cascade activation. Furthermore, endogenous H2S can react with CuHF to produce CuS nanoparticles with strong chemodynamic/photothermal effect and to release metal porphyrin ((Cu)HMME) with photodynamic effect, as the second-cascade activation. When CuHF/DATS@HMON is accumulated at the tumor site through EPR effect, DATS in the CuHF/DATS@HMON can react with endogenous glutathione (GSH) in cancer cells to in situ generate H2S, and then H2S can vulcanize CuHF to generate CuS nanoparticles and (Cu)HMME complexes, thus realizing chemokinetic, photodynamic and photothermal multi-mode therapy to inhibit tumor growth. At the same time, the tetrasulfide bonds (−S-S-S-S-) in HMON allow the material to be slowly broken down and metabolized. Therefore, this study not only provides a general design for constructing tumor-microenvironment-responsive agents, but also provides some insights for multi-modal therapy of cancers.