Design,Synthesis And Synergistic Anti-Tmour Application Of Several Multifunctional Inorganic Photothermal Nanomaterials

Photothermal therapy(PTT)as a spatiotemporally controllable tumor treatment model has attracted extensive attention from researchers in related fields.Nanomedicine-based PTT utilizes photothermal conversion agents(PTAs)to convert light energy into heat energy under near-infrared(NIR)light irradiation,which can cause local hyperthermia to eliminate tumors.With the advantages of non-invasiveness,high selectivity and low cost,PTT has made remarkable progress in the field of cancer treatment.Nowadays,the design and development of high-efficiency and safe nano-PTAs have become the core scientific problem of nanomedicine-based PTT.At present,the as-reported PTAs including noble metal nanomaterials,metallic chalcogenides,two-dimensional materials,organic small molecules,semiconductor polymers,etc.,have shown excellent multifunctional anticancer diagnostic and therapeutic application prospects.However,PTT faces both challenges and opportunities in its future clinical transformation due to the low photothermal conversion efficiency,insufficient tumor accumulation,inevitable thermal damage to normal tissues and organs around the lesion,long-term retention in vivo,and tumor recurrence and metastasis,tumor heat resistance,the limitations of monotherapy,etc.Therefore,in view of these practical problems in the transition from basic scientific research to clinical application,this paper mainly carries out the following research work:(1)Although many semiconductor nanomaterials have demonstrated photothermal conversion properties,the low photothermal conversion efficiency limits their further clinical applications.Therefore,in order to improve the photothermal conversion efficiency of rare earth vanadate semiconductor(CeVO4,NdVO4),we constructed noble metal/semiconductor heterojunction nanocomposites(CeVO4/Ag,NdVO4/Au).The existence of enhanced localized surface plasmon resonance(LSPR)effect and abundant electron transition pathways in the interface of noble metal and semiconductor increases the optical absorption of rare earth orthovanadates in the visible/near infrared(Vis/NIR)region,which results in the improved photothermal conversion efficiency and reactive oxygen species(ROS)generation ability.Cellular experiments and in vivo antitumor experiments show that noble metal/semiconductor heterostructures upon 808 nm laser irradiation significantly inhibit the growth of primary malignant tumors.(2)Due to the complex tumor microenvironment(TME)and distal metastatic lesions,single PTT based on PTAs with high photothermal conversion efficiency is difficult to completely cure cancer.Meanwhile,the excitation light source of the first NIR biological window limits the expansion of clinical application of PTT.Herein,we fabricate a multifunctional cascade bioreactor based on Cu2MoS4(CMS)loaded with glucose oxidase(GOx).The CMS has strong absorption in the second NIR II biological window,and it can produce remarkable PTT and photodynamic therapy(PDT)effect under the excitation of 1064 nm laser.The existence of redox couples(Cu+/Cu2+and Mo4+/Mo6+)in CMS enables it react with hydrogen peroxide(H2O2)to to achieve excellent chemo-dynamic therapy(CDT)effect.Meanwhile,CMS with enzyme activities can relieve hypoxia and consume overexpressed GSH in tumors to enhance CDT effect.The GOx loaded in CMS can achieve synergistic starvation therapy by consuming the glucose inside the tumors.When CMS@GOx combined with checkpoint inhibitor CTLA4 antibody,the nanomedicine could induce strong immune responses for both eliminating primary tumors and suppressing cancer metastasis.The vaccine-like CMS@GOx nanomedicine with enzyme activities achieves impressive synergistic PTT/PDT/CDT/starvation therapy/immunotherapy with high efficiency.(3)During the process of PTAs circulating in vivo to the leisions,there is a certain amount of residual PTAs in normal tissues nearby leisions.Unintended damage always occurs when light penetrates healthy tissues with the aggregation of PTAs.Thus,constructing TME-activated PTAs with phototthermal conversion performance only in tumor sites,which can avoid the harm to normal tissues.Herein,in response to overexpressed endogenous H2S and slightly acidic CRC TME,we design metabolizable core-shell Cu2O@CaCO3 nanosystem to achieve "turn-on"synergistic therapies.The acidic decomposable CaCO3 as protective shell can prevent Cu2O from being sulfuretted by endogenous H2S in normal tissues before reaching the CRC sites.When Cu2O@CaCO3 reaches the CRC sites,the CaCO3 protective shell decomposes under acidic TME and releases calcium ions.Subsequently,the exposed Cu2O reacts with overexpressed endogenous H2S to generate ultrasmall Cu31S16.It can achieve 1064 mm stimulated PTT(supplemented with PDT/CDT/calcium overload treatment),resulting in prominent therapeutic effect on the removal of colorectal tumors.After treatment,ultrasmall Cu31S16 can be metabolized out of the body in urine by the renal filtration system,avoiding the harm caused by long-term retention of inorganic nanoparticles in the body.Further,in combination with CD47 checkpoint blockade,the immunosuppressive TME can be reversed by re-educating the pro-tumoral M2 phenotype tumor-associated macrophages(TAMs)to tumoricidal MI phenotype TAMs.Consequently,the T cells-mediated immune responses are initiated,which can effectively inhibit the growth of invasive tumors and distal secondary tumors.Therefore,CRC TME-activated Cu2O@CaCO3 can achieve precise and high-efficiency"stimuli-responsive" colorectal tumors treatment.(4)To completely ablate tumors during PTT,the temperature of cancerous tumors is often raised to more than 50?.Such high temperature could not only eliminate the tumors but also injure surrounding healthy tissues nearby leisions.To circumvent the issue,scientists exploit mild PTT at low-temperature(38-43 ?)to induce cancer cells death.However,its therapeutic effect is not ideal,because the cancer cells can activate their own protective pathways,such as overexpressed heat shock proteins(HSPs),to quickly repair mild hyperthermia-caused cell damage.Therefore,it's extremely necessary for future clinical translation to maximize the effect of PTT while minimizing the damage on healthy tissues and organs by adopting appropriate therapeutic temperature.Here,we report ferroptosis-induced low-temperature PTT based on Pd single atom nanozyme(Pd SAzyme).The Pd SAzyme with maximized atomic utilization efficiency(-100%)show excellent peroxidase(POD)and glutathione oxidase(GSHOx)activities.Meanwhile,Pd SAzyme with strong absorption in the whole NIR region can realize 1064 nm excited PTT.Due to the dual POD and GSHOx enzyme activities,Pd SAzyme can effectively cause the accumulation of OH and inactivation of glutathione peroxidase 4(GPX4)protease,resulting in the occurrence of ferroptosis.The large amount of lipid peroxidation(LPO)and ROS generation during ferroptosis can effectively cleave HSPs,enabling Pd SAzyme-regulated mild PTT for ablating malignant tumors in a significant way.This study clarifies the role of ferroptosis in promoting mild PTT,providing an effective and safe strategy for PTT.Also,it enlightens new research ideas for temperature controlled mild PTT in the future.