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The Anti-tumor Effect Of Multifunctional NIR-mexitecan Nano Liposomes

Posted on:2020-01-15Degree:DoctorType:Dissertation
Country:ChinaCandidate:J XingFull Text:PDF
GTID:1364330611994766Subject:Biomedical engineering
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At present,chemotherapy is still the mainstream way of clinical anti-tumor treatment.However,most of the chemotherapeutic drugs are insoluble,and the bioavailability and specificity of drugs for tumor tissue are poor,resulting in unsatisfactory therapeutic effects and big side effects.Therefore,improving the therapeutic effect and reducing toxic and side effects are key issues that need to be solved in tumor treatment.Liposomes,a single-chamber or multi-compartment vesicle structure composed of a lipid bilayer,have been developed for more than 50 years.They have attracted attention as therapeutic drug carriers for bioactive substances.The development of liposomes has gone through a long process.The real breakthrough occurred in the past 20 years,and a variety of liposome drugs have been approved by the FDA.Scientists' interest in this field is still high.As a relatively mature drug delivery system,liposomes can be modified to achieve active targeting,on-demand controlled release,medical assisted imaging and other functions,bringing new hope for the treatment of tumors.Photosensitive liposome is a new type of intelligent liposome.It converts light energy into heat energy under the action of photosensitizer,and controls the release of drugs.At the same time,it also cooperates with photodynamic therapy and tumor imaging.The photosensitive liposome can solve the solubility problem of chemotherapeutic drugs,significantly improve the anti-tumor treatment effect combined with photothermal and photodynamic therapy,overcome the drug resistance and side effects caused by chemotherapy,and realize the integration of diagnosis and treatment.7-Ethyl-10-hydroxycamptothecin(SN38)is an active metabolite of camptothecins,and its anti-tumor activity is hundreds of times or even more compared with that of irinotecan(CPT-11),which is already used in clinical.However,SN38 has a poor solubility in many biocompatible solvent,making it unusable for clinical use.In order to improve the solubility of SN38 and expand its application range,we designed a near-infrared photosensitive liposome encapsulating a fat-soluble SN38 prodrug(moeixitecan,MXN-003)to achieve controlled release for combined therapy.The specific research contents are as follows:In the first part,moeixitecan was encapsulated in liposomes,and moeixitecan liposomes with good physical and chemical properties were obtained with optimized prescription.The encapsulation efficiency can reach 90.25%,and SN38 can be slowly released in vitro.It has high anti-tumor activity and has passive targeting of tumors.In addition,molecular dynamics simulation was used to deeply analyze the conformation of moeixitecan in phospholipid bilayer,and the relationship between structural characteristics and drug efficacy of lipid prodrugs was preliminarily elucidated.In the second part,a near-infrared photosensitive liposome containing moeixitecan was developed.Organic photosensitive materials with good biocompatibility are widely used in pharmaceutical carriers.The near-infrared fluorescent probe,indocyanine green(ICG),has attracted extensive research interest as an organic photosensitizer that has been approved for clinical use by the FDA.ICG and moeixitecan were encapsulated in thermosensitive liposomes to prepare multifunctional NIR-moeixitecan liposomes for the combined treatment and imaging of tumors.The results show that ICG is encapsulated in liposomes,which can reduce the quenching of ICG and enhance its fluorescence intensity and photosensitivity.The near-infrared moeixitecan liposome can release the drug under the illumination of the near-infrared laser to achieve controlled release of the drug.The photothermal and photodynamic effects of ICG combined with therapeutic effect of moeixitecan can greatly enhance the anti-tumor activity,the tumor inhibition rate can reach 96.8%,and the tumor is basically ablated.In the third part,due to the poor stability of the aqueous solution of ICG,there exist a problem of aggregation quenching in the carrier.A novel near-infrared probe,DSPE-IR623(ICG derivative IR623 is conjugated to DSPE with amido bond)was synthesized.Fluorescent liposomes(iLPs)with different size were prepared by using DSPE-IR623 as membrane materials,and the effects of the liposome size on distribution in cells and in vivo were studied.The results confirmed that the fluorescent probe was effective for tracing liposomes.Compared with liposomes containing near-infrared fluorescent dyes,multifunctional liposome prepared by DSPE-IR623 can be more easily prepared,better quantify the content of near-infrared dyes and prevent leakage of near-infrared dyes,which is conducive to the encapsulation of other drugs by liposomes.
Keywords/Search Tags:Near-infrared fluorescent dye, moeixitecan, Photodynamic therapy, Photothermal therapy, Tumor imaging, Combination therapy, Nano-liposomes
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