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The Study On Photo-sensitive Liposomes With A Controlled Release Of Doxorubicin Via The Mediation Of Near Infrared Ray

Posted on:2019-02-19Degree:DoctorType:Dissertation
Country:ChinaCandidate:Q P LiFull Text:PDF
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The targeted accumulation of drugs into lesion site mediated by drug delivery system,as well as the real-time drug controlled release in the site,is an effective means to increase drug treatment efficacy and reduce side effects.In this study,the anti-human epidermal growth factor receptor 2 antibody(HER2ab)was first successfully prepared by a cloning and recombination technology.We presented two designs which could realize the controlled release of drugs via the mediation of near-infrared(NIR)light,and the combination therapy to HER2-positive tumors.A novel drug-controlled release liposome system responsing to photodynamic therapy mediated by near-infrared light was designed.The liposomes showed NIR light-sensitive properties which contained a special phospholipid material(1-(1Z octadecenyl)-2-oleoyl-sn-glycero-3-phosphocholine,PLsPC)and a photosensitizer Indocyanine Green(ICG).Doxorubicin hydrochloride(DOX),as a model anti-tumor drug,was encapsulated into the liposomes,and the surface of liposome was further modified with anti-HER2 antibody,inducing a specific binding to high-HER2 expressing tumor cells.The constructed liposomes(HER2-I&D-LSL)can generate a large amount of reactive oxygen species(ROS)under near-infrared irradiation,causing a photodynamic therapy effect to tumors.The generated ROS further can induce the break of the vinyl ether linkage in PLsPC molecules.As a result,the phospholipid molecule loses a hydrophobic lipid chain which causes the disorder of the membrane structure of the liposomes,triggering the release of DOX from the liposomes and exerting a chemotherapy effect to the tumors.The ability of producing ROS was investigated for HER2-I&D-LSL under the NIR light irradiation.It was found that DOX release from the liposomes was mainly related to the proportion of PLsPC and ICG-ODA in the membrane,as well as the irradiation conditions.The liposomes could be effectively taken up by tumor cells.Because their surface were conjugated with anti-HER2 antibody,HER2-I&D-LSL showed significantly higher internalization and accumulation into cancer cells and tumors with high HER2 receptor expression,respectively.After the accumulation of HER2-I&D-LSL into cancer cells,DOX release presented an obvious increase under the irradiation of near-infrared light,inducing an increasing free DOX concentration inside the cells.The generated ROS and the released DOX under NIR light irradiation induced the simultaneous photodynamic and chemotherapeutic effects,resulting in significantly damaged cancer cell in vitro compared to chemotherapy or photodynamic therapy alone.Furthermore,compared to I&D-LSL,as non-targeting liposomes,HER2-I&D-LSL exhibited significantly stronger antitumor activity to high-HER2 expressing cancer cells due to the mediation of HER2 receptor.Our data also demonstrated that the dual photodynamic and chemotherapeutic effects of HER2-I&D-LSL combined with NIR irradiation clearly caused the strongest inhibition of tumor growth compared to photodynamic and DOX chemotherapy alone.Importantly,HER2-I&D-LSL presented a significant lower systemic toxicity due to its specific tumor accumulation and DOX release limited in tumor site.In this study,DOX and HAuNS with near-infrared photothermal conversion ability were further encapsulated in liposomes.HER2ab was also modified on the surface of the liposomes.The obtained liposomes(HER2-DOX-PSL)also exhibited NIR light-sensitive properties with photothermal effect.In order to achieve the high encapsulation of HAuNS,octadecy 1-3-mercaptopropionate(OMP)was used to modify the surface of HAuNS inducing the increase of hydrophobic property of the particles.Under NIR laser irradiation,HER2-DOX-PSL produced an obvious photothermal conversion,leading to the rapid release of DOX from the liposomes.A dual-tumor model was built in nude mice bearing both HER2 positive and negative tumors.It was found that obviously more accumulation of the liposomes were observed in HER2 positive tumors compared to HER2 negative tumors after i.v.injection.HER2-DOX-PSL under NIR laser irradiation produced strong anti-tumor activity in vivo with tumor suppression efficiency up to 92.7%,which was significantly higher than photothermal therapy and chemotherapy alone,mainly attributing to the increased accumulation in HER2 positive tumors,as well as the combined effects of photothermal and chemotherapy.More importantly,HER2-DOX-PSL showed significantly lower systemic toxicity compared to the non-targeted liposomal DOX-PSL,mainly because of the decreased dose of DOX,less drug accumulation in normal tissues and lower NIR irradiation power.Our work presented the new designs of photosensitive liposomes,which could achieve NIR light-mediated drug triggered release and multiple combination therapy to tumors.And it may provide a new possible approach for the safe and effective treatment of tumors.
Keywords/Search Tags:Near-infrared light, Photodynamic therapy, Photothermal conversion, Chemotherapy, Photosensitive liposomes, Triggered release, Active-targeted therapy
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