The Construction Of Ultra-small Janus Nanocomposites And Their Application In Tumor Therapy

In recent years,nanomaterials have been widely utilized in cancer therapy with the development of nanomedicine.However,traditional nanomaterials with a single function suffer from insufficient tumor target accumulation,poor therapeutic effect,and low biometabolic rate.Multifunctional nanomaterials are urgently required to enhance anti-tumor therapeutic effects.Among them,ultrasmall-sized Janus nanoparticles have received wide attention due to their multimodal co-treatment of tumors,strong tissue penetration,and in vivo metabolic ability.In this study,three different multifunctional nanocomposites were constructed based on ultrasmall Janus nanoparticles,and their anti-tumor therapeutic effects were investigated.(1)Dual-targeting nanocomposite for synergistic enhancement of sonodynamic and chemotherapeutic effects.The multifunctional nanocomposite TiO2x@NaGdF4@IR780@LND-HA(TNILH)was constructed based on ultra-small Janus nanoparticles TiO2-x@NaGdF4(TN NPs)loaded with the acoustic sensitizer IR780 and hexokinase II inhibitor lonidamine(LND)and encapsulated with hyaluronic acid(HA).TNILH has the following advantages:a)Ultra-small sized nanoparticles provided enhanced tissue penetration and in vivo metabolism;b)TN NPs achieved spatial separation of nanodrug and imaging material,effectively reducing signal interference and attenuation,which enabled better implementation of magnetic resonance imaging-guided cancer therapy;c)The accurate delivery of nano-drug was achieved by utilizing the specific targeting of tumor cells by HA and the targeted delivery of mitochondria by IR780;d)Under ultrasound radiation,the dual acoustic sensitizers TN NPs and IR780 synergistically contributed to the production of reactive oxygen species(ROS),disrupting intracellular redox homeostasis and inducing cell damage;meanwhile,LND inhibited mitochondrial respiration by inhibiting the activity of hexokinase Ⅱ,which cooperated with ROS to accelerate the process of apoptosis.The studies have shown that the TNILH had excellent anti-tumor therapeutic effects.(2)Ultra-small Janus nanoparticle for multimodal imaging-guided tumor synergistic therapy.A novel Janus nanoparticle MnFe2O4@NaGdF4(MG NPs)with an average diameter of only 7.7 nm was prepared by a simple one-pot method.Subsequently,small molecule immune inhibitor NLG919 and HA were loaded onto DSPE-PEG-NH2 to construct a multifunctional nano-composite material MnFe2O4@NaGdF4@NLG919@HA(MGNH).MGNH targeted into tumor cells via HA and utilized the inherent characteristics of ultra-small nanoparticles to enhance tissue penetration and in vivo metabolism.MG NPs have photoacoustic imaging and T1/T2 dual-mode imaging capabilities.After 808 nm laser irradiation,it showed not only the excellent photothermal conversion performance;but also was able to catalyze endogenous H2O2 to generate ROS and deplete overexpressed reduced glutathione(GSH)in the tumor microenvironment(TME)which amplified oxidative stress.Meanwhile,NLG919 could reduce the number of regulatory T cells,reverse the immunosuppressive microenvironment,and improve the immunotherapeutic effect.The studies have shown that MGNH integrated photothermal therapy/chemodynamic therapy/immunotherapy,which could achieve multi-modality imaging-guided combination of tumor therapy.(3)Applications of ultra-small Janus nanocomposite in tumor sonodynamic,chemodynamic,and starvation synergistic therapy.Ultra-small Janus nanoparticles ZnFe2O4@TiO2(ZT NPs)were synthesized by a simple one-pot method.After administration of ultrasound radiation,ZTNPs not only had excellent acoustodynamic therapeutic effects;but also catalyzed the production of ROS from endogenous H2O2 and depleted the overexpressed GSH in TME,prompting cell damage.Subsequently,the multifunctional nanocomposite ZnFe2O4@TiO2@Orl@CHC-FA(ZTOCF)was successfully constructed by DSPE-PEG-NH2 adsorbed with orlistat(Orl)and linked with α-cyano-4-hydroxycinnamic acid(CHC)and folic acid by amide bonding.After entering tumor cells via folate targeting,ZTOCF would be degraded by the acidic environment in the lysosome and released Orl and CHC,which were respectively fat and lactate transporter inhibitors.Afterwards,Orl and CHC synergistically inhibited tumor energy metabolism and improved the effect of starvation therapy in a fastingmimicking diet environment(a low protein.low sugar,high fat diet strategy).The experiments showed that ZTOCF could achieve synergistic effects of sonodynamic therapy,chemodynamic therapy and starvation therapy.effectively inhibiting the proliferation and migration of cancer cells.