Liposomal Nano-Reactors For Tumor Microenvironment Moduation And Combination Therapy Of Cancer

Cancer(malignant tumor)is one of the serious diseases that menace human health continually.While the complex pathogenesis of cancer results in the failure of traditional therapeutic methods(surgery,radiotherapy,chemotherapy)which can't satisfy the increasing cancer cases' need of high quality cancer therapy.Therefore,development of new safe and high-efficiency therapies receive wide focus in cancer treatment research.Recently,along with the accumulation of research experience in clinic cancer treatment,researchers realize that the growth microenvironment of tumor(especially solid tumor)not only induce the tumor development and metastasis but also seriously limit tumor response for common therapeutic methods(e.g.radiotherapy,chemotherapy),which has become one of main reasons for tumor treatment failure.Over the past 20 years,the rapid development of nanotechnology provides the new thinking and base of materials in tumor treatment strategies.Liposome,a kind of bilayer vesicle by the self-assembly of amphipathic molecule,with great biocompatibility,excellent pharmacokinetic profiles and versatile drug loading abilities,has been extensively explored and applied as nano-drug carrier.Among these,liposome based nanomedicines are the firstly approved and most widely clinical used nanomedicines(e.g.Doxil,Dauno Xome),which achieve good therapeutic effects for various human diseases.Hence,in this paper,we use liposome as carrier,utilizing the catalytic ability of catalase(CAT)and glucose oxidase(GOx),design and synthesis two kinds of novel liposomal nano reactors with clinic transformation ability,by regulating the tumor hypoxia microenvironment,which can increase the curative effect of radiotherapy and chemotherapy to achieve safe and high-efficiency combination therapy.The main research contents and conclusions as follows:1.In the first work,focusing on the treatment efficiency of traditional radiotherapy and chemotherapy seriously limited by tumor hyoxia microenvironment,we design and synthesis a kind of liposomal nano reactor that can both improve tumor hypoxia and enhance chemotherapy,at the same time,combined with radiotherapy to enhance the synergistic chemo-radiotherapy.Contents as follows: By amidation reaction,hydrophilic cisplation prodrug(Pt(IV))is conjugated 1,2-distearoyl-sn-glycero-3-phosphoethanolamine(DSPE)to format amphiphilic cisplatin prodrug lipid molecule(Pt(IV)-DSPE),then self-assemble 1,2-dipalmitoyl-snglycero-3-phosphocholine(DPPC),cholesterol,and polyethylene glycol(PEG)conjugated DSPE(DSPE-m PEG5k)to form Pt(IV)-liposome,following loaded with catalase to achieve CAT@Pt(IV)-liposome.Utilizing the catalase catalyze H2O2 into O2,CAT@Pt(IV)-liposome can decompose endogenic H2O2 into O2 after accumulating to tumor,which can improve the tumor hypoxia.At the same,comparing with cisplatin,CAT@Pt(IV)-liposome can decrease the side effect of cisplatin with same chemotherapeutic efficiency.Combined with X-ray radiation,CAT@Pt(IV)-liposome can enhance chemo-radiotheray efficiently,achieve safe and high-efficacy tumor treatment.2.In the second work,based on the highly demand for glucose and oxygen due to rapid tumor growth and mechanism,and the specific hypoxia activated toxicity of biological reduction drug,we design and synthesis a glucose oxidase(GOx)based liposomal nano reactor(GOx@liposome),then combine with biological reduction drug(Banoxantrone,AQ4N)which has specific toxicity to hypoxia tumor cells,which result in synergistic combination of hypoxia-activated therapy and starvation therapy.In our study,GOx@liposome can transfer intratumoral glucose and oxygen into gluconic acid and H2O2 after accumulating to tumor which promotes the progression of tumor hypoxia;on the other hand,AQ4 N,as hypoxia-activated drug,can only kill hypoxic tumor cells.Therefore,GOx@liposome can increase the toxicity of AQ4 N.The combination of GOx and AQ4N(glucose and O2 exhaust,cell toxicity of H2O2 and chemotherapeutic toxicity)inhibit the tumor growth multiply and strongly.In this paper,we design two kinds of liposomal nano reactors,and apply them for two kinds of novel combination tumor therapies,by regulating the tumor hypoxia microenvironment,which achieve safe and high-efficiency tumor combination treatments.Comparing with traditional nano drug carriers,our liposomal nano carrier systems are simple and bio-safe,with good clinic transformation potential.At the same time,our strategies are novel and have high treatment efficiency,which can bring new thinking in nanomedicine research.