Constructing Intelligent Nanovehicles And Their Applications In Cancer Therapy

Cancer is one of the most deadly deseases of human beings.It is popular to fight against cancer with intelligent nanomedicines.As a result,nano materials are required to be modified to satisfy the biology and clinical requirments.In previous studies,researchers focused on various molecules modified on the nanoparticles to achieve biological effects and therapeutic efficacy,ignoring the methods of chemical modification which can significantly influence the property of nanoparticles.In this thesis,we mainly explored the surface modification of nanoparticles by small molecules,polymers and cell membrane,constructing intelligent nanovehicles and comparing their morphology,biological effects and therapeutic efficacy.Accordingly,we optimised these nanoparticles or nano-assemblies to achieve better cancer therapy efficacy and practical applications.Binding strategies significantly influence the anti-cancer activity of chemo-drugs,such as doxorubicin(Dox).It is reported that there are two chemical linkers for conjugating Dox on nanoparticles including the hydrazine bond and amide bond.However,there is no comparison sdudy on these two linkers.Hence,we conjugated Dox and gold nanoparticles(GNP)with hydrazine bonds and amide bonds separately,and compared the differences on drug loading,drug release,delivery efficiency and in vivo anti-cancer activity.As a result,we could figure out conjugation of Dox via hydrazine bonds was optimal,and provided references for drug conjugation and surface modification.Constructing nano-assemblies is an effective way to improve the properties of nanoparticles.Stimuli-responsive degradation of nano-assemblies can satisfy the bio-clearance of living bodies.In this study,we employed dithiol-PEG to construct nano-assemblies by crosslinking through S-S and Au-S bonds.We explored the influence of morphology with different ratios of dithiol-PEG and thiol-PEG,and studied the degradation in the high glutathione concentration.Moreover,we illustrated the advantages of nano-assemblies by cellular uptake and enhanced photothermal effect.This assembling strategy was suitable for gold nanoparticles with different sizes.In addition,we modified the nano-assemblies with pH sensitive Dox,EGF peptide and Cy5.5,to develop the multifunctional nanovehicles with drug release,tumor targeting,fluorescent imaging and therapeutic effects.This study presents a feasible strategy for building nano-assemblies conveniently,enhancing the therapeutic property of spherical gold nanoparticles.Magnetic nanoparticles(MNP)realize controllable and intellegent response to magnetic field with good tissue penetration.In order to enhance the anti-cancer activities,Dox should possess the capability to escape lysosomes and enter nuclei.MNP were modified with hyaluronic acid(HA)and Dox to prepare magnetic field responsed intelligent nanovehicles.The hydrazine bonds conjugated Dox released sensitively in the acidic condition;MNP could interrupt the lysosomes through rotating magnetic field to enhance the anti-cancer activity.In this study,MNP was modified with HA and Dox for tumor targeting and sensitive drug release,combining physical and chemical therapy for efficient cancer treatment.Mitochondria-targeted nanovehicles can improve the efficacy of cancer therapy.Triphenylphosphine(TPP)modification can effectively realize mitochondria targeting of nanoparticles.As a result,we modified GNPs with TPP to achieve assembled GNPs for mitochondria-targeted photothermal therapy.Cancer cell membrane was employed to improve mitochondria targeting through membrane fusion.Assemblies were targeted to mitochondria by TPP,realizing precise photothermal therapy;Cancer cell membrane could target original cancer cells and accelerate the mitochondria targeting process.Combining with TPP and cancer cell membrane,GNPs realized multifunctional self-assemblies and enhanced anti-cancer efficacy.In summary,this thesis explored the modification and construction of intelligent nano vehicles,and investigated their forming mechanism,surface modification properties and intelligent responses to stimuli.Herein,we pointed out an appropriate strategy for Dox conjugation and applied it in GNPS assemblies which improved the anti-cancer efficacy effectively.Moreover,magnetic nanoparticles facilitated Dox escaping from lysosomes and efficiently inhibit the tumor growth.Additionally,the GNPS modified with TPP and cancer cell membrane could improve mitochondria-targeted photothermal therapy.