Synthesis And Anticancer Applications Of Several Novel Black TiO₂ Based Multifunctional Nanocomposites

Traditional cancer treatment,mainly including chemotherapy and radiotherapy,has seriously affected the treatment effect and postoperative health of patients due to its long treatment period,large toxic side effects on human body,and easy to appear drug resistance.Therefore,it is urgent to find more precise,safe and controllable anticancer methods to assist or replace traditional treatments.Recently,near infrared light(NIR)and ultrasound(US)have attracted much attention due to their non-intrusive,deeper penetration and high spatial/temporal resolution.The novel cancer diagnosis and treatment modes triggered by NIR and US has specific spatial/temporal selectivity and minimally invasive,which can greatly improve the defects of traditional cancer treatment.With advances in nanotechnology,many functional nanomaterials based on light/acoustic stimulation have been extensively studied in the field of cancer theranostic.Among them,titanium dioxide(TiO2)nanomaterials,as one of the most important and classical metal oxides,have the advantages of low price,stable structure,high catalytic activity and safety to human and environment.They have been widely used in many biological related fields such as sterilization,protein separation/purification,medical imaging,cancer therapy and so on.Whereas titania is a wide band gap semiconductor(3.0?3.2 ev)and its absorption threshold is in the ultraviolet(UV)region,which limits its application in NIR excited antitumor phototherapy.Furthermore,the rapid recombination of electrons and holes in light/acoustic-activated TiO2 also affects their catalytic activity.Therefore,improving the NIR absorption capacity of TiO2 and increasing the defective species in the crystal structure are of great significance for improving their overall chemical reaction performance and the expansion of applications.In addition,how to skillfully combine titanium dioxide with light/acoustic stimulation of cancer diagnosis and treatment mode in order to achieve more ideal efficacy,has a high research value in the field of novel nano-cancer therapy.This work is based on modified black TiO2 to explore the multifunctional diagnostic and therapeutic applications of novel TiO2 matrix composites in the field of light/acoustic-stimulated cancer therapy by combining other functional nanomaterials and loading new drugs.Researches have focused on the following:1.In order to enhance the light conversion effect and magnetism of titanium dioxide,multifunctional Fe@?-Fe2O3@H-TiO2 nanocomposites with multi-layer core-shell structure were synthesized by one-step hydrogenation reduction,which showed remarkably improved magnetic and photoconversion effects as a promising generalist for photocatalysis,bio-imaging and photothermal cancer therapy(PTT).The deep defects(such as Ti3+,-OH et al.)were produced on the white TiO2 surface in hydrogenated reduction progress and the white color of TiO2 into black forming hydrogenated TiO2(H-TiO2),thus increasing the absorption of titanium dioxide in the Vis/NIR region and then enhancing its solar catalytic activity.The Fe@?-Fe2O3 magnetic core was introduced to makes it convenient for separating and recovering the catalytic agents.More importantly,Fe@y-Fe2O3@H-TiO2 nanocomposites show enhanced phototheconverts rmal conversion efficiency due to more circuit loops for electron transitions between H-TiO2 and ?-Fe2O3.At the same time,the magnetic core endows the nanocomposite magnetic targeting and MR imaging abilities.Thus,the reported core/shell nanocomposites can be served as a NIR-responsive photothermal agent for magnetic-targeted photothermal therapy,as well as a multi-modal imaging probe for cancer including the infrared photothermal imaging,magnetic resonance imaging and photoacoustic imaging.2.In order to improve the utilization of light energy and overcome the negative effect of tumor hypoxic environment on the antitumor therapy,black mesoporous titanium dioxide(BMT)with large pore size(?8 nm)was designed and synthesized as a novel carrier loaded with alkyl radical(·R)generation drug(AIBI)to form BMT@AIBI nanocomposites.Meanwhile,phase change material 1-tetradecyl alcohol is used as pore plugging agent to block loaded AIBI drug below 38?(melting point),and the loaded drug will be released when above 38?.BMT as a light transducer can convert near-infrared(NIR)light energy into thermal and chemical energy(·OH),promoting photothermal therapy(PTT)and photodynamic therapy(PDT),respectively.Simultaneously,AIBI will be thermally decomposed into alkyl radicals by the heat generated from BMT for thermodynamic therapy(TDT).The high concentration of free radicals produced by BMT@AIBI nanocomposites resulted in DNA double-strand breaks(DSBs)and ultimately induced cancer cell apoptosis.Because the production of free radicals is independent of oxygen,the BMT@AIBI NCs with NIR irradiation presented excellent in vitro and in vivo anticancer results under hypoxic conditions.Therefore,The reported NIR-induced platform based on BMT@AIBI NCs,which could perform triple energy conversion processes containing light energy to thermal energy,to chemical energy,and to thermal energy then to chemical energy,realizes synergetic photo-thermal-dynamic therapy(PTT,PDT and TDT)to overcome the problem of tumor hypoxia for enhanced anticancer effects.3.In order to achieve better antitumor therapeutic efficacy and inhibit tumor metastasis,US with higher tissue penetration was selected as exogenous stimulus and arginine(LA,a natural source of NO gas)was selected to be loaded into black mesoporous titanium dioxide(BMT)to form BMT@LA "nano-vaccine".US stimulation can not only promote drug penetration and release,but also simultaneously trigger BMT and LA to produce singlet oxygen(1O2)and NO,respectively.Notably,1O2 from US-triggered BMT can promote LA oxidation to produce more NO.The high concentration of 1O2 and NO causes intracellular strong oxidative stress(OS)and DNA double-strand breaks(DSBs),and ultimately induced cancer cell apoptosis.The US triggered BMT@LA "nano-vaccine" combining with immune checkpoint inhibitor PD-L1 antibody,can trigger strong anti-tumor immune response thus effectively kill and inhibit primary and metastatic tumors.Hence,BMT@LA based "nano-vaccine" can realize synergetic sonodynamic/gas/immunotherapy with enhanced antitumor therapeutic effects.