Synthesis of Magnetic Silver-Iron Oxide Nanocomposites and Its Applications in Anti-tumor Study

Author:Liu Er Gang

Supervisor:yang zhi min gong jun bo


Degree Year:2017





The developing nanotechnology and its applications in medicine had renewed the concepts of both cancer diagnosis and therapy during the past 30 years,which had made prominent contributions in clinical cancer researches.However,despite of the various kinds of nano-vehicles,the overall tumor loads was minimal,being calculated as low as 0.7%(median).In this thesis(1st chapter),We had made a thorough review on the history as well as the current status of nanomaterials mediated cancer drug delivery.Based on the anatomical facts,we attributed the delivery inefficiency of traditional delivery systems to low efficient EPR effect and slowly tumor uptake.Furthermore,we proposed that a dual functional vehicle with correspondingly improved EPR effect as well as enhanced tumor uptake would warrant a substantially improved tumor targeting efficiency.In the 2nd chapter,we prepared two kinds of silver nanoparticles by a gentle reduction method.Of note,silver nanoparticles immobilized by cyclodextrin was ease for modification and suit to be utilized as middle-product for further functionalization of silver nanoparticles with advanced structures.Whereas dextrin coated silver nanoparticles was inert to thiol binding and protein adsorption,which would thus facilitate extended blood circulation and enhanced targeting efficiency via EPR.In the 3rd chapter,we modified the dextrin coated silver nanoparticles with thiolated cell penetrating peptide and Cy5,which were then tested for their cellular uptake and tissue penetration potential.The results demonstrated that both TAT and LMWP could promote cellular uptake of the modified silver nanoparticles.In vivo organ distribution assay demonstrated that CPP could promote its modified nanoparticles to be engulfed by almost all kinds of organs/tissues.Whereas RES remained the primary targets for both CPP modified and unmodified silver nanoparticles.In the 4th chapter,we designed and synthesized 3-mercaptopropanohydrazide as a linker.The linker could bind to silver nanoparticle via silver-thiol bondage at one hand,and react with doxorubicin to from a hydrazone bond on the other hand,which permitted it to be released in a pH-dependent pattern.We tested the intracellular release behaviors of drug loaded nanoparticles.Results demonstrated that drug loading nanoparticles could release more drugs at acidic regions of cytosols.In chapter 5,we crosslinked silver nanoparticles with iron oxide nanoparticles by a sequential in situ capping method.The as-prepared hybrid nanoparticles were further modified with CPP to promote its translocation across the membrane barriers.The dual functionalized nanoparticles were then assessed for their brain delivery potential.Results demonstrated that 1)either CPP or external magnetic field could independently help enhance brain accumulation of the given particles(with increase of 2.6-and 3.9-folds,respectively,as compared with free dyes);2)The two could synergistically work together and render more efficient delivery.In chapter 6,we tested the tumor delivery efficiency as well as anti-tumor effect of Tat-FeAgNPs.The results demoststrated that 1)In the tumor delivery test,TatFeAgNP-Cy5 accumulated at the tumor site most efficiently.By analyzing fluorescence of organ homogenates,it was demonstrated that TAT and the external magnetic field could synergistically work together and promoted tumor accumulation of Tat-FeAgNPCy5,which displayed the most efficient tumor load.ICP-MS test depicted the tumor retained Tat-FeAgNP-Cy5 accounted for 6.7 ± 2.4 % of the injected dose.2)In vivo anti-tumor effect of the doxorubicin loaded silver nanoparticles showed that TatFeAgNP-Dox was most competent in combating the tumor burdens.