Preparation Of Functional Polyphenol Self-Assemblies And Their Anti-Tumor Applications

The prevention and treatment of malignant tumors has become the focus of current research.However,the complex microenvironment of tumor sites,such as high expression of reactive oxygen species(ROS),microacidity,and hypoxia,aggravates tumor invasion and metastasis,increases tumor drug resistance,and limits the efficacy of many therapeutic options.In this context,it is important to develop novel antitumor drugs by modulating or even exploiting the tumor microenvironment to improve the therapeutic efficacy of tumors.In this work,two functional polyphenol nanoparticles are proposed to overcome the influence of tumor microenvironment on tumor therapy through ternary synergistic therapy and enhanced DOX therapy,respectively,to enhance the therapeutic effect.we here construct a mitochondria-targeted nitric oxide nanogenerator EArg Fe@Ce6 with high loading content of the NO donor L-Arginine(L-Arg)to achieve synergistic photodynamic/gas/photothermal therapy upon the single 660 nm light irradiation.The coordination of EGCG and ferric ions(Fe3+)provides EArg Fe@Ce6 supreme photothermal capability to perform low-temperature PTT(m PTT).EGCG endows EArg Fe@Ce6 with mitochondria-targeting capability and meanwhile favors hypoxia alleviation for enhanced PDT.The PDT-produced massive reactive species(ROS)further catalyzes L-Arg to generate a considerable amount of NO to perform gas therapy and sensitize both m PTT and PDT.The in vitro and in vivo results show that the single 660 nm-triggered synergistic photodynamic/gas/photothermal therapy can achieve excellent tumor therapeutic outcomes.One-pot nanoconstruction(HEBD)is fabricated based on the chemical reactions driven assemblies among epigallocatechin gallate(EGCG),buthionine sulfoximine(BSO)and formaldehyde in aqueous mediums followed by Dox adsorption.Acid tumor microenvironments allow the liberation of EGCG,BSO,and Dox due to the breakage of Schiff base bonds.EGCG component in HEBD is responsible for targeting mitochondria and disrupting mitochondrial electron transport chain(m ETC)to compel electrons leakage in favor of their capture by Dox to produce more ROS.EGCG-induced m ETC disruption results in mitochondrial respiration inhibition with alleviated hypoxia in tumor cells while BSO inhibits glutathione biosynthesis to protect ROS from redox depletion,further boosting Dox-induced CDT.This strategy of amplifying CDT pathway for the Dox-mediated combined therapy could largely improve antitumor effect,extend lifespan of tumor-bearing mice,reduce risks of cardiotoxicity and metastasis.In summary,this study proposes the idea of using functional polyphenol-amino acid self-assembled nanomedicines,which has important implications for developing or even exploiting the tumor microenvironment for novel antitumor therapies,with great practical application in biomedical applications.