Synthesis Of Thermo-sensitive Nanomedicine Assembly For Synergistic Antitumor And Its Intratumoral Delivery Performance Properties

Cancer,also known as malignant tumor,has gradually becoming the first killer of human health due to its high incidence and low survival rate.Combined chemotherapy with radiation therapy or immunotherapy have become a new method and direction of clinical cancer therapy.Although this combination has achieved certain results,most chemotherapy drugs lack the tumor targeting and selectivity,which result to less efficiency and severe side effects.Over the past decades,the use of nanotechnology to nanometer small molecule chemotherapy drugs has improved the above-mentioned deficiencies to some extent.Nanomedicine can not only achieve high enrichment of drugs at the tumor field by using the enhanced Permeability and Retention?EPR?which is unique to the tumor field,but also effectively reduce the systemic toxicity of drugs.However,due to the unique pathophysiological characteristics of solid tumor tissues,such as disordered vascular system,interstitial fluid pressure and dense extracellular matrix?ECM?,which provide natural barriers for the tumor.It is difficult for the large-sized nano drug to further penetrate into solid tumor tissues,but it is more likely to overcome the higher interstitial fluid pressure inside the tumor,pass through the gap of the dense tumor extracellular matrix,so have advantages in deep penetration.Focusing on problems above,we designed a nano drug with programmed thermo-sensitive at the tumor to achieve high-efficiency tumor treatment.It is expected to improve the in-depth delivery ability of the loaded chemotherapeutic drug by the dimensional change of the assembly.Specifically,the“large”size nano drug carrier enter the blood circulation then the near-infrared light is applied to the tumor.The thermal stimulation induces tumor vasodilation,which effectively increases the enrichment of the nano drug at the tumor field by the EPR effect,meanwhile,contributes to subsequent intratumoral infiltration of the drug.More importantly,the photothermal intelligent response nano drug is designed to release the charge reversed and the size smaller than 5 nm nano drug under thermal stimulation.Thereby this design realizes effective in-depth delivery and uptakes of therapeutic drugs to tumor cells.The main research contents are as follows:?1?The amphiphilic thermo-sensitive polymer chain PCL₄₀₀₀-Azo-PAMAM/Pt was constructed,and the thermo-sensitive nano drug assembly hCluster/PAMAM/Pt@IR780 and other control groups were synthesized by nanoprecipitation and homogenized.The physicochemical properties of the above synthesized products were characterized by nuclear magnetic resonance spectroscopy,ultraviolet absorption spectroscopy,fluorescence spectroscopy,transmission electron microscopy,dynamic light scattering,etc.,followed by stability,responsiveness,response mechanism,photothermal properties,drug release and many other aspects.Mutual verification to understand its performance indicates that hCluster/PAMAM/Pt@IR780 undergoes size and potential conversion under mild photothermal 47?stimulation with concomitant generation of non-oxygen-dependent free radicals R·.?2?In vitro anti-tumor and in-depth delivery effects of the thermo-sensitive nano drug assembly hCluster/PAMAM/Pt@IR780.We explored the biotoxicity parameters of Pt,IR780,R·and the constructed organic polymer carrier of hCluster/PAMAM/Pt@IR780 to ensure low nanocarrier toxicity and high synergistic nano drug tumor cells killing effect.In addition,we used the constructed 4T1 3D multicellular spheroids to simulate the solid tumor environment to explore the in-depth delivery effect of hCluster/PAMAM/Pt@IR780 on the tumor,and obtained the expected results.At a mild photothermal temperature of 47?,hCluster/PAMAM/Pt@IR780 undergoes a change in size and potential to effectively penetrate into the interior of multicellular spheroids.?3?Study on the tumor enrichment and synergistic antitumor effects of the thermal-sensitive nano drug assembly hCluster/PAMAM/Pt@IR780 at the body level.hCluster/PAMAM/Pt@IR780 was injected into the mice through the tail vein,using a near-infrared 808 nm laser to maintain mild photothermal heat at 43?for 10 min.After 24 h of metabolism,IVIS imaging was performed.The results were mild photothermally treated mouse tumor nanometers.The amount of particle enrichment is about 2 times higher than that of the non-photothermal treatment.Next,we explored the effect of hCluster/PAMAM/Pt@IR780 and other controls on body-level tumors,hCluster/PAMAM/Pt@IR780 in Pt chemotherapy,mild photothermal PTT at 47?and production of non-oxygen-dependent free radicals R·The PDT effect shows an effective tumor treatment effect.In this thesis,a near-infrared 808 nm laser-mediated thermo-sensitive nano drug assembly hCluster/PAMAM/Pt@IR780 was constructed,which was achieved by combining drug therapy enrichment and improving the tumor microenvironment.Ultimately,efficient enrichment,site-specific release,in-depth delivery of drugs at the tumor,and synergistic effects of PTT,PDT and chemotherapy further significantly improve the therapeutic effect of the tumor.