Construction and Antitumor Efficiency Study of Tumor Microenvironment-Responsive Drug/gene Nano-delivery Systems

Author:Chen Wei Liang

Supervisor:zhang xue nong

Database:Doctor

Degree Year:2018

Download:298

Pages:113

Size:8361K

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Recent years,Nano-delivery systems(NDSs)have been deeply developed,due to the advantages towards traditional antitumor agents.In order to achieve an efficient tumor targeting delivery,NDSs should get through various physical barriers.However,different physical and chemical properties of NDSs are required in each delivery process.Based on the special microenvironment of tumor,smart NDSs with changeable physical and chemical properties were designed for the tumor drug/gene delivery.In this study,three kinds of microenvironment-responsive NDSs were designed for the tumor drug/gene delivery and the advantages of them in the treatment of tumor were explored.Chapter 1: The development of tumor targeting NDSs and the application of microenvironment-responsive NDSs were briefly introduced.And the advantage of the combination of gene and drug therapy for tumor was expounded.The research background and the design ideas of this paper were based on the review.Chapter 2: Chitosan(CS)was modified with p Hi-responsive urocanic acid and p He-responsive 2,3-dimethylmaleic anhydride(DMMA)to prepare DA-CS-UA.The p H-responsive study showed that the DA-CS-UA NPs(DA-NPs)exhibited p He-triggered charge reversal behavior and p Hi-triggered size expansion.DOX loaded DA-NPs(DOX/DA)were prepared with suitable particle size and high encapsulation efficiency(EE%)and drug-loading content(DLC%)of DOX.Additionally,these DOX/DA exhibited rapid DOX release under p Hi conditions.Compared with that at p H 7.4,DOX/DA exhibited a higher cellular uptake and penetration in 3D tumor spheriods at p He.The NPs exhibited a significant co-location with the acidic endo/lysosome,and DOX could release and diffuse to nuclei.In vivo,DA-NPs exhibited a good tumor target effect and inhibited the growth of tumor significantly.Besides,these NPs reduced the accumulation of DOX in normal tissues and reduced the systemic side effects of DOX.Therefore,DOX/DA exhibited satisfied tumor-target effect and antitumor effect in vivo,which enhanced the antitumor effect of DOX and reduced the side effects.Chapter 3: In order to further improve the tumor targeting effect in vivo,we designed programmed p H/reduction-responsive NPs for the delivery of antitumor agents.The NPs were composed of reduction-responsive core(DOX/LCL)which was modified with lactobionic acid(Lac)and PEG layer(PEG-CS-DA,sPEG)which exhibited p He-triggered charge reversal behavior.Under the physiological condition,the positively charged DOX/LCL was coated with sPEG to prepare sPEG-DOX/LCL.However,the charge of sPEG reversed from negative to positive at p He.As a result,the sPEG was detached,leading to the exposure of positive charge and Lac ligand.Additionally,sPEG-DOX/LCL exhibited rapid release of DOX when GSH was added.At p He,sPEG-DOX/LCL exhibited higher cellular uptake and better penetration effect than p H 7.4.After internalization,DOX released rapidly from sPEG-DOX/LCL,triggered by intracellular GSH and led to the apoptosis of tumor cells.In vivo,sPEG-DOX/LCL exhibited prolonged circulation time and improved targeting effect.Also,sPEG-DOX/LCL showed enhanced antitumor effect and reduced side effect in vivo.Therefore,these programmed p H/reduction-responsive NPs provided a strategy for the efficient delivery of antitumor agents in vivo due to the enhanced tumor-target and antitumor effects.Chapter 4: In order to further improve the antitumor effect,low-density lipoprotein biomimetic NPs were prepared by mimicking the composition of human LDL and used for the loading of siVEGF and DOX.Then siVAGF/DOX-NPs were coated with sPEG to prepare sPEG-siVEGF/DOX-NPs.In response to p He,the sPEG layer was detached,leading to the exposure of positive charge and active ligand Apo B protein,which enhanced the cellular uptake and endosome escape.And the intracellular VEGF protein was down-regulated by siVEGF,which limited the proliferation and migration of HUVEC cells.On the other hand,after internalization,DOX released from NPs and diffused to nuclei,leading to the apoptosis of tumor cells.In vivo,these NPs exhibited excellent tumor-target effect and DOX as well siRNA could be delivered to tumor tissues.The antitumor effect study demonstrated that sPEG-siRNA/DOX-NPs could inhibit the tumor growth and angiogenesis efficiently,and exhibited a better antitumor effect than sPEG-siRNA-NPs and sPEG-DOX-NPs.Therefore,co-delivery of siVEGF and DOX with the tumor microenvironment-responsive NPs provide a good strategy for the efficient antitumor effect in vivo.