Controllable Construction Of Micro-nano Structure Of Mn O₂ Drug Carrier And Study On Drug Release Performance And Mechanism

Cancer has become a massive disease threatening human life and health.As a common therapy for cancer treatment,chemotherapy has not only shown obvious side effects,the therapeutic effect is also affected by the complex microenvironment of tumor cells.Nano-drug carrier has offered chances for obtaining ideal chemotherapy effect because of its various outstanding advantages.In recent years,nanostructured MnO₂ has attracted broad attention in the field of anticancer drug delivery because of its excellent performance matching the tumor microenvironment.However,the MnO₂ nano-drug carrier suffers not only the lack of specific structure conducive to drug loading but also functional barriers and the unclear mechanism of drug loading and release.The preparation of nano-drug carrier and drug release are essentially the construction of micro-nano structure and mass transfer process of micro-nano interface.Therefore,through the controllable construction of MnO₂micro-nano structure,this paper realizes the efficient drug loading and functional modification of nanocarriers,systematically studies the multi-responsive drug release of nano-drug carriers,biological evaluation and enhancing the effect of chemotherapy,and combines the research advantages of computer simulation at the micro-nano interface,the drug loading and degradation mechanism of MnO₂ nano-drug carrier were explored.Major research contents are listed below:（1）The construction of micro-nano structure can realize the efficient loading of anticancer drugs and the multi-responsive drug release.Targeting on the lack of specific structure conducive of drug loading,this chapter proposed a preparation method of MnO₂with mesoporous pore structure,coated gold nanorod（Au/MnO₂）with photothermal conversion ability and proposed the preparation method of"core-shell"nano-drug carrier with mesoporous MnO₂ as coating layer.Then,taking the antitumor drug doxorubicin hydrochloride（DOX）as the model drug,the photothermal conversion performance,drug loading and multi-responsive drug release performance of Au/MnO₂ nano-drug carrier were investigated.The results show that mesoporous MnO₂ is very conducive to the loading of DOX（the drug loading efficiency is as high as ca.99.1%）.Au/MnO₂ nano-drug carrier has glutathione（GSH）/p H/near-infrared（NIR）-responsive drug release performance and excellent photothermal conversion ability.This chapter provides a new idea for the construction of MnO₂ nano-drug carriers.（2）Construction and biological evaluation of nano-drug carrier based on functionalization of micro-nano interface.This chapter verifies that there are functionalized hydroxyl（-OH）functional groups on the surface of mesoporous MnO₂ prepared in（1）.In addition,it is reported that nano-drug carriers with a size of 50 nm-120 nm have more clinical application value.Therefore,in this chapter,the reduced size（1）nanocarriers（GNR/MnO₂）were modified,and then poly（N-isopropylacrylamide-co-acrylic acid）（GNR/MnO₂/PNA）with dual p H and temperature response was grafted.In this chapter,the photothermal conversion and degradation properties of nanocarriers were studied.Meanwhile,DOX was used as a model drug to explore the killing effect of nanocarriers on human breast cancer cell line（MCF-7）,human hepatocellular carcinoma cell line（Hep G2）,and human normal liver cell line（L02）.Biological evaluation of the inhibition of migration and invasion of cancer cells and mitochondrial damage were carried out.The results imply that GNR/MnO₂/PNA nanocarrier could selectively kill cancer cells with little negative effect on normal cells.This chapter modifies mesoporous MnO₂ and widens the road of functional utilization of MnO₂nano-drug carriers.（3）Construction of hollow MnO₂/GNPs micro-nano structure and multi-responsive drug release.In order to further expand the application scope of the construction method of"core-shell"drug carrier with mesoporous MnO₂ as coating.In this chapter,with SiO₂ as the core and mesoporous MnO₂ as the shell,the surface of MnO₂ was modified and connected with inorganic gold nanospheres（GNPs）.Finally,nano-drug carriers（MnO₂/GNPs）with hollow and mesoporous structures were obtained by dissolving SiO₂ with Na₂CO₃ solution.Taking the antitumor drug DOX as the model drug,the photothermal conversion performance,drug loading performance,multi-responsive drug release performance,and drug release kinetics of hollow MnO₂/GNPs nano-drug carriers were studied.This chapter has reference significance for the construction of"core-shell"drug nanocarriers with mesoporous MnO₂ as coating and other nanostructures as core.（4）Drug loading and degradation mechanism of MnO₂ nanocarrier.Almost all MnO₂nano-drug delivery studies emphasized the importance of biological evaluation.However,the drug loading process and degradation mechanism in tumor microenvironment are not clear.Firstly,the drug loading and degradation mechanism of MnO₂ nano-drug carrier in（1）-（3）chapters were studied by computer simulation.After analysis,MnO₂ nano-drug carrier can efficiently load antitumor drugs through electrostatic interaction,hydrogen bond,and van der Waals interaction.In the degradation process,there is a"transition state"in the process of MnO₂ capturing"H"on sulfhydryl（-SH）of GSH,which directly affects the degradation rate of the nanocarrier.This chapter can guide the drug loading and adjust drug release efficiency of MnO₂ nano-drug carrier.（5）In situ construction of PGA/CDDP@MnO₂micro-nano structure and controlled drug release.Cisplatin（CDDP）is particularly easy to combine with sulfhydryl（-SH）substances,resulting in inactivation.In this chapter,nanostructured MnO₂ acts as an intelligent"gatekeeper"to prevent premature leakage of CDDP and enhance the effect of chemotherapy.First,γ-PGA/CDDP conjugate was synthesized by the coordination reaction between-COOH on polyglutamic acid（PGA）and Cl atom on CDDP.Then,PGA/CDDP nanoparticles were constructed by electrostatic interaction.Finally,MnO₂ shell in-situ coated PGA/CDDP nanoparticles（PGA/CDDP@MnO₂）were constructed by the redox reaction between KMnO₄and the residual carboxyl group of PGA/CDDP nanoparticles.While nanoparticles achieve multi-responsive drug release,MnO₂ shell can efficiently consume GSH to enhance the killing effect of CDDP.The results prove that the killing effect of PGA/CDDP@MnO₂nanoparticles on human lung cancer cells（A549）is 2-3 times as that of CDDP.At the same time,PGA/CDDP@MnO₂ nanoparticles can also inhibit the migration and invasion of A549cells.