Construction Of Multifunctional Nano-sized Drug Delivery Carriers And Its Applications In Tumor Targeted Diagnosis And Therapeutics

Cancer is a kind of malignant tumor with biological characteristics such as invasion and metastasis due to abnormal cell differentiation and proliferation.The rapid development and high mortality of cancer pose a major threat to human health.Therefore,accurate diagnosis and effective treatment of cancer is an urgent goal of modern medicine.In the recent decades,clinical studies have found that different individuals with the same type of tumor have different responses to the same treatment,which brings great challenges to tumor treatment.Therefore,it is urgent to develop more safe and effective treatment methods to improve the therapeutic efficacy of tumor and the quality of life of patients.Thanks to the rapid development of nanotechnology in recent decades,a variety of nano-materials have come out one after another.The unique physical and chemical properties of nano-materials show great potential in molecular imaging,sensing,and new model treatment intervention.Inorganic nano-materials have highly functionalized surfaces,which provide new possibilities for developing advanced diagnostic and therapeutic drugs and improving the detection and treatment level of major diseases.Aiming at the difficulties in tumor therapy and nano drug construction,based on inorganic nano-materials,combined with aptamers and natural cell materials,the following researches were carried out around the design and construction of multi-functional tumor targeted nano-diagnosis and therapeutic systems.(1)In order to improve the therapeutic effect of tumor,a nano-assembly with tumor targeting and multi-mode synergistic therapy was constructed.In Chapter 2,gold nanorods with excellent photothermal conversion properties were used as basic carriers and the surface was functionalized by layer by layer assembly.First,the thiol-group modified nucleotide sequence was attached to the surface of gold nanorods by Au-S covalent bond.Then,according to the principle of DNA base complementary pairing,the aptamer AS1411 was further assembled on the surface of nanoparticles,so as to obtain the nano-system which can target and recognize the highly expressed nucleolin on the surface of tumor cells.Chemotherapy drug DOX and photosensitizer TMPy P4 were used as drug models and were respectively loaded into GC base pairs in DNA complementary sequences and G-quadruplex formed by aptamer AS1411 by π-πstacking.Finally,the targeting dual-drug delivery nano therapeutic system was obtained.Relevant research results show that the nano t herapeutic system has good stability,can effectively target tumor cells and give a light-triggered multi-mode synergistic therapy which inhibit the proliferation of tumor cells and overcome the treatment bottleneck caused by drug resistance of tumor cells.(2)In view of the difficulties in the construction of nanodrugs for personalized treatment of tumor,with the help of the biological function related advantages of natural cell materials,a biomimetic nano-drug with homologous tumor cells targeting ability was constructed from the perspective of bionics.In Chapter 3,a core-shell structure composed of magnetic nanoparticle cores and mesoporous silica shell layers was synthesized through solution-gel process.Moreover,near-infrared photosensitizer ICG was loaded into the shell layer by electrostatic interaction to obtain nanoparticles that can be used in magnetic resonance imaging and photothermal treatment.Finally,the drug-loaded nanoparticles were encapsulated in tumor cell membrane fragments to gain a biomimetic nano-drug which can target to homologous tumor cells.Relevant studies have shown that compared with the non-natural materials modified nanoparticles,the biomimetic nanoparticles were superior in targeting homologous tumor cells and photothermal therapeutics,which can effectively solve the difficulties in the construction of targeted functional modules of nano-drugs for personalized cancer treatment.(3)Due to the complex physiological environment of organism,nanodrugs,as exogenous substances,will face the clearance of various biological barriers in blood circulation,which reveals a negative effect on diagnosis and treatment.In Chapter 4,the 4T1 tumor cell bearing mice were established as animal model,the tumor-targeting and photothermal therapeutic effect was further studied in vivo based on the work of Chapter 3.Relevant research results show that the biomimetic nano-drug has good histocompatibility,and its distribution in the body can be monitored in real time by near infrared fluorescence imaging.In addition,under the protection of tumor cell membrane debris,the biomimetic nano-drug can effectively accumulate in the tumor site and show good photothermal conversion effect,which has obvious inhibitory effect on the growth of tumor tissue.