Hydrogen Peroxide Responsive Nanomedicine For Enhancing Oxidative Stress In Breast Cancer

Breast cancer is a heterogeneous disease with inherent molecular heterogeneity,which largely influences treatment decisions.The subtypes of breast cancer present a common clinical characteristic,but with markedly differences in histological expression and medical prognosis.The molecular features of breast cancer have important implications,which is a driving principle for modern-day treatments toward breast cancer,resulting in improved therapeutic efficacy.Of note,the tumor microenvironment,as a common feature shared among different subtypes of breast cancer,has also shed the light on the treatment for breast cancer that independent on its molecular features.Asa consequence,the development of universal strategies for breast cancer therapy might also favor its clinical outcomes.Since 1993,the photodynamic therapy（PDT）has gained clinical approval for the treatment of serval cancers among various countries.The on-demand singlet oxygen（¹O₂）generation via PDT upon laser irradiation could cause severe oxidative damage for cancer cells.The clinical trials of PDT for breast cancer therapy have witnessed promising advances,including high therapeutic efficacy,low systematic toxicity and suitability for different subtypes of breast cancer.Though an innovation strategy,PDT is hindered by the inherent hypoxia of tumor.Therefore,major emphasis for PDT needs to be put on its ¹O₂ yielding ability in tumor.Moreover,the metastasis of breast cancers is the cause of death in almost all patients,but PDT processes limited efficacy for metastatic sites because of the low penetration and fixed irradiation area of laser.Herein,light-independent therapeutic strategies based on the generation of reactive oxygen species（ROS）to induce oxidative damage for cancer are highly desired.First,the amino-functionalized metal-organic frameworks（NH₂-MOFs）were discovered as novel and universal templates for the constriction of porous gold nanoshell(NH₂-MOFs@Au_Shell),which process light responsive photothermal ability（PTT）and cargo loading/delivery performance.The encapsulation of catalase-mimicking platinum nanoparticles（Pt NPs）in NH₂-MOFs（Pt@UiO-66-NH₂）enabled this nanomaterial with O₂-evolving in presence of H₂O₂ in tumor.After porous Au_Shellcoating,Pt@UiO-66-NH₂@Au_Shell was enriched with PTT ability.The further loading of Chlorin e6（Ce6）,a photosensitizer,in Pt@UiO-66-NH₂@Au_Shell(Pt@UiO-66-NH₂@Au_Shell-Ce6,PUA-Ce6)achieved a combined PTT and PDT.PUA-Ce6 presented an excellent synergistic tumor therapeutic performance with a 100%elimination of breast tumors.Second,encouraged by catalytic activity of Pt NPs for benefiting the PDT,an organized in situ catalytic cascades reaction driven by the dual nanozymes-engineered porphyrin metal-organic frameworks（PCN）was fabricated.The Pt NPs were sandwiched by PCN（Pt@PCN@Pt,P@Pt@P）,and outer-shell of which was further embedded with glucose oxidase-mimicking ultrasmall gold nanoparticles（AuNPs）and coordinated with folic acid（P@Pt@P-Au-FA）.The P@Pt@P-Au-FA could catalyze the intratumoral H₂O₂ to O₂ for（1）enhancing the O₂ dependent PDT,and（2）subsequently accelerate the depletion ofβ-D-glucose for synergistic starving-like therapy with the self-produced H₂O₂ as the substrate.Consequently,a remarkably enhanced synergistic therapeutic strategy with prevention of tumor recurrence and metastasis was achieved.Third,considering the limitation of laser（e.g.penetration depth,less suitability for metastatic sites）for PDT/PTT,a biocompatible PEGylated arsenene nanodots（AsNDs@PEG）with high monoelemental arsenic purity were discovered as a new-concept arsenical drug that can selectively and effectively treat solid tumors.The intrinsic selective killing effect of AsNDs@PEG was closely related to highly oxidative stress in tumor cells,which led to an activated valence-change of arsenic（from less toxic As⁰ to severe toxic oxidation states）,followed by decreased superoxide dismutase（SOD）activity and massive reactive oxygen species（ROS）production.These effects occurred selectively within cancer cells,causing mitochondrial damage,cell-cycle arrest and DNA damage.Additionally,the newly discovered on-demand photothermal properties of AsNDs@PEG facilitates the elimination of the tumors without recurrence,potentially further expanding their clinical utility.In line of the practicability for a large-scale fabrication and negligible systemic toxicity（even at high doses and with repetitive administration）of AsNDs@PEG,a proof-of-principle evidence of a new-concept arsenical drug was provided with high therapeutic efficacy for selective solid tumor therapy.