Design And Application Of Tumor Microenvironment Responsive Photothermal Nanomaterials

Taking advantage of the specificity of tumor microenvironment to treat tumor through photothermal nano materials can effectively improve the effect of tumor therapy,and reduce the toxicity and side effects to human body.At present,tumor diagnosis and therapy using gold nanorods have advanced gradually to clinical trial stage.Whereas,the clinical application of photothemal materials is still restricted because of the moderate targeting ability of materials,the need of multiple dosing administration and other key issues.The research in this dissertation focus on the design of two kinds of novel photothermal materials utilizing tumor microenvironment to improve the systematic circulating ability and tumor targeting ability of the material.The research provides new insights into tumor-targeted photothermal therapy.The dissertation is comprised of four chapters.Chapter one introduces cancer and photothermal therapy,and summarizes the development of photothermal therapy,the targeted delivery of photothermal nanometer materials,and the design of noval materials.Platinum(Pt)nano materials,which have good photothermal properties and biocompatibility,can get prepared using mature methods.In the present study,there are many approaches to synthesize Pt nanoparticles with good morphology,such as spheres,dendrites and rods.Therefore,we choose to use platinum nanomaterials and transport them to be accumulated in tumor tissues through targeted delivery,then treat tumor with photothermal therapy.Hyaluronic acid(HA)is a kind of material with good biocompatibility and active tumor targeting ability.It can specifically recognize the cluster determinant 44(CD44)receptor overexpressed by cancer cells,and it is widely used in the design of tumor targeting materials.However,in most researches,the modification of extra groups on the surface of HA or the formation of conjugates is needed,making the synthesis process over complicated.Enhanced permeability and retention(EPR)effect can take the suit size nanoparticles to the tumor tissue.But the low accumulation efficiency and extensive distribution require us to make further improvements on the materials.Compared with the normal human tissues(pH 7.4),the extracellular of tumor(pHe 6.5)shows different pH gradients.In chapter two,we utilize HA as a template to synthesize Pt nanoparticles and gain HA-encapsulated Pt nanoparticles(HA/Pt).Through this simple and efficient method,we synthesize Pt nanoparticles with good morphology and uniform size.After comparing HA/Pt with the alginate acid-encapsulated Pt nanoparticles(AA/Pt),which is synthesized using the same method,we find that HA/Pt has high efficiency in tumor targeting,and shows excellent effect of photothermal therapy.Furthermore,in the therapy of nude mice subcutaneous tumor model,HA/Pt is shown to inhibit tumor growth effectively.In chapter three,we use a green method to synthesize generation five(G5)polyamidoamine(PAMAM)dendrimer-encapsulated Pt nanoparticles(G5-Pt),and modifies it with Maleic anhydride(MAH),further gains G5-Pt-MAH,a photothermal material with pH responsive ability.After comparing it with G5-Pt-SC,which is modified with succinic anhydride(SC)and does not have charge reversing ability,we find that G5-Pt-MAH is able to solve the elimination problem in systematic circulation via its electronegativity.After the shedding of MAH(because of the pH gradient outside the tumor),G5-Pt-MAH can accomplish charge-reversal,thus enhancing its accumulation in tumor areas.The photothermal therapy of nude mice tumor model further proves the charge-reversing ability of the material;meanwhile,it is shown to effectively inhibit tumor growth.The final chapter summarizes the full dissertation,and gives perspectives of Pt photoerhmal nano materials with tumor targeting ability in clinical applications.Although Pt photoerhmal nano materials are not yet approved as clinical dosage forms,we can prospect from the biocompatibility and development of photothermal therapy,that they will be used in clinical cancer therapy someday through advanced researches and complete understanding of the mechanism.When facing with problems which cannot be solved by chemotherapy and radio therapy,targeted photothermal materials may bring some new sights.