Low concentrations of endogenous hydrogen peroxide (H2O2) and intrinsic oxidative stress defense system greatly limited the efficiency of Fenton and Fenton-like reactions driven by a single metal element. Moreover, the complex physiological environment and inherent self-healing function of tumors make it difficult for chemodynamic therapy (CDT) alone, driven by Fenton and Fenton-like reactions, to eliminate malignant tumors. Herein, a tumor microenvironment (TME) remodeling cobalt-stannous sulfide CoSnS2 (CSS) hollow nanocubes are presented for photothermal therapy (PTT)-improved CDT, in which two redox pairs (Co2+/Co3+ and Sn2+/Sn4+) are involved in catalyzing H2O2 to generate a large number of toxic hydroxyl radicals (˙OH) resulting in massive apoptosis of tumor cells. Importantly, two redox pairs (Co2+/Co3+ and Sn2+/Sn4+) promoted the depletion of glutathione (GSH), which reduced tumor antioxidant capacity and thus enhanced the CDT therapeutic impact of CDT. Furthermore, the CDT efficiency was greatly improved by the excellent photothermal effect (η = 47.23%). The combination of PTT and CDT achieved good therapeutic effects, which may provide a new perspective for the development of other anti-tumor strategies on the basis of improved CDT and modulation of TME.
Yudi Deng,Zhijie Jiang,Yincheng Jin,Jianan Qiao,Shan Yang,Hui Xiong,Jing Yao
Detrimental tumor microenvironment (TME) relies on distorted tumor vasculature for further tumor expansion. Vascular normalization therapy partly improves TME through vessel repairing, while these therapies enter an unbreakable Möbius ring due to each attempt hindered by pro-angiogenic factors from TME, leading to limited duration and extent of vascular normalization. Here, we developed a nanosystem including FLG and MAR/MPA nanodrugs to regulate both tumor vasculature and TME. FLG nanodrugs were constructed by connecting VEGF/VEGFR2 inhibitory low molecular weight heparin and gambogic acid with F3 peptide decoration for directly regulating on vascular endothelial cells and inducing vascular normalization. Meanwhile, MAR/MPA nanodrugs encapsulating CCL5/CCR5 blocker maraviroc were designed to restrict cytokine functions of angiogenesis and TME deterioration, contributing to vasculature repairing and TME reconstruction. Our results demonstrated this combined nanosystem synergistically induced vascular normalization window lasting 9 days and restored vascular permeability and oxygen supply in Panc-1 tumor. Furthermore, in melanoma, our nanosystem achieved immune improvements with increased infiltration of CD4 + and CD8 + T cells in a remodeled TME. The two nanodrugs assisting each other in terms of both vascular repairing and TME improvements successfully reversed the vicious crosstalk to a positive one, achieving overall TME remodeling and promoting therapeutic efficiency.
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