Chemotherapy And Gas-Therapy In Combination With Phototherapy Of The Treatment Tumor

Cancer is the most malignant disease and the first leading cause of mortality in the world.Commonly used cancer therapeutics including surgery,chemotherapy and radiotherapy have many limitations,such as the severe side effects and the unsatisfactory therapeutic effect.It is urgent to propose a novel and effective cancer therapy method.In the past several decades,nanomedicine has been extensively explored for chemodrug delivery,because of their desired capabilities to enhance the drug solubility,promote tumor accumulation,control drug release,and reduce side toxicity.Particularly,varieties of stimuli-responsive nanocarriers have been developed to realize the selective anti-cancer efficacy via "on demand" drug release in response to stimuli.While great achievements have been made,the non-specific drug release during circulation or in normal tissues is often inevitable.To address these issues,one promising approach is to regulate the tumor microenvironment by generating artificial signals in tumor tissues/cells using external stimuli.Cancer phototherapy,including photodynamic therapy and plotothermal therapy,has received wide attention in recent years due to its non-invasiveness,high selectivity and controllability.In this thesis,we choose phototherapy to regulate the other cancer thcapy to achieve the safer and more effective cancer therpy.We explored the application of phototherapy-mediated remote control of chemotherapy and gastherapy,which may be able to reverse the tumors drug resistance and achieve synergistic anticancer therapy.The contents and conclusions of this thesis are sumarized as follows:Chapter 1:The chapter presents a brief overview on the current status of caner therapy,the tumor microenvironment,the responsive chemodrugs and nanocarriers,the photodynamic therapy(PDT),chemotherapy,photothermal therapy(PTT),gas therapy,especially the carbon monoxide(CO)therapy and their synergistic therapyChapter 2:Stimuli-responsive nanomedicine(NM)with an on-demand drug release property has demonstrated promising utility toward cancer therapy.However,sensitivity and cancer selectivity still remain critical challenges for intelligent NM,which will compromise its therapeutic efficacy and lead to undesired toxicity to normal tissues.Herein,we report a convenient and universal approach to spatiotemporally control the chemodrug release via the photodynamic therapy(PDT)-mediated alteration of the tumor microenvironment.An arylboronic ester(BE)-modified amphiphilic copolymer(mPEG-PBAM)was designed to form micelles and encapsulate doxorubicin(Dox)and hematoporphyrin(Hp).The Dox/Hp co-encapsulatedmicelles(PB-DH)were stable under noirnal physiological environment.In contrast,under tumor-specific light irradiation,extensive reactive oxygen species(ROS)will be generated from Hp in the tumor sites,thus quickly dissociating the micelles and selectivelyreleasing the chemodrug Dox as a consequence of the ROS-mediated cleavage of the hydrophobic BE moieties on the polymers.As such,synergistic anti-cancer efficacy was achieved between the Dox mediated chemotherapy and the Hp-mediated PDTChapter 3:Polymeric micelles have demonstrated wide utility for chemodrug delivery,which however,still suffer from short comings such as undesired drug loading,disassembly upon dilution,pre-leakage of drug cargoes during systemic circulation,and lack of cancer-selective drug release.Herein,a poly(ethylene glycol)(PEG)-polyphosphoester-based,reactive oxygen species(ROS)-responsive,core-cross-linked(CCL)micellar system was developed to encapsulate both chemodrug(Dox)and photosensitizer(Ce6).The hydrophobic core of the micelles was cross-linked via a thioketal(TK)-containing linker,which notably enhanced the drug loading and micelle stability.In tumor cells,far-red light irradiation of Ce6 generated ROS to cleave the TK linkers and disrupt the licelle cores.As such,micelles were destabilized and Dox release was promoted,which thereafter imparted synergistic anti-cancer effect with ROS-mediated photodynarnic therapy.Chapter 4:Bioreductive chemodrugs require hypoxic conditions to activate their anti-cancer efficacy.The insufficient and heterogeneous hypoxic condition in tumor tissues hurdles the therapeutic potency of bioreductive chemodrugs.We herein report a NIR light-triggered CO release system based on mesoporous Prussian blue nanoparticles(PB NPs)to enable cancer-selective hypoxia aggravation and hypoxia-responsive activation of bioreductive anti-cancer drug,tirapazamine(TPZ).Pentacarbonyl iron(Fe(CO)5)was coupled to PB NPs via coordination interaction,and TPZ was encapsulated into the pores of PB NPs.To prolong blood circulation and improve tumor accumulation,the PB-CO-TPZ NPs were surface-decorated with PEG-NH2.Upon tumor site-specific light irradiation,the non-lethal photothermal effect of PB NPs released CO,which accelerated mitochondrial oxygen consumption and generated hypoxia to activate TPZ.The CO-induced mitochondrial exhaustion simultaneously led to cancer cell apoptosis,thus realizing synergistic anti-cancer effect with TPZ-mediated bioreductive chemotherapy.Chapter 5:Multidrug resistance(MDR)is the main cause of chemotherapy failure,and the mechanism of MDR is largely associated with drug efflux mediated by the adenosine triphosphate(ATP)-binding cassette transporters.Herein,a NIR light-triggered CO release system based on mesoporous Prussian blue nanoparticles(PB NPs)was developed to reverse MDR via CO-induced metabolic exhaustion.Pentacarbonyl iron(Fe(CO)5)as the CO producer was coupled to PB NPs via coordination interaction,and doxorubicin(Dox)was encapsulated into the pores of-PB NPs.After laye-by-layer(LBL)coating,the NPs showed desired serum stability to enhance tumor accumulation.Upon tumor site-specific NIR light(808 nm)irradiation,the non-lethal temperature elevation cleaved the Fe-CO bond to release CO.CO then expedited mitochondrial metabolic exhaustion to block ATP synthesis and inhibit AxTP-dePendent drug efflux,thus reversing MDR of the Dox-resistant MCF-7/ADR tumors to potentiate the anticancer efficacy of Dox.At the meantime CO-mediated mitochondrial exhaustion could upregulate the pro-apoptotic protein,caspase 3,thus inducing cellular apoptosis and enabling synergistic anticancer effect with chemotherapy.Chapter 6:Photodynamic therapy(PDT)is broadly applied in clinical fields owing to the non-invasion and selectivity.However,lower efficiency of PDT limited its clinical application.Mitochondria are extensively researched as the target sites to maximize PDT effects because of their crucial roles in metabolism.Here,a light-activated nanoplatform for delivering carbon monoxide(CO)(HSA-CO-Ce6)is fabricated to realize the enhanced PDT.Metabolomics studies reveal that CO could target to mitochondria specifically,accelerate their respiration and act as a novel capacity in generation of intracellular reactive oxygen species(ROS).The over-consumption strategy induces the dysfunction of mitochondrial and then dramatically reduces the intracellular ATP concentration and obvious increase in cytochrome c oxidase activity.The mitochondria damage is also accompanied with the activation of the apoptosis signals(caspase 3),whose level is directly correlated to the apoptosis extent.In summary,this thesis proposes a universal strategy for the programmed cancer therapy and expands the cancer therapy methods,providing a reference for the green,safe and efficient cancer treatment.Chapter 7:Overviews the thesis and gives a future perspective in the field.