Construction Of Multifunctional Iron Based/Mesoporous Silica Nano-Drug Systems And Their Application In Tumor Therapy

Malignant tumor has become one of the major diseases that seriously threaten human health.Chemotherapy is the most common and important method for the treatment of advanced tumors,but chemotherapy has two fatal defects.Firstly,first-line clinical chemotherapy drugs?such as paclitaxel,doxorubicin,etc.?cannot specifically identify tumor cells,have severe side effects and excessively inhibit the immune system,causing severe tissue damage such as bone marrow suppression and cardiotoxicity.Secondly,clinical treatment requires tumor cells to accumulate enough drugs and be sensitive to drugs.However,in the process of chemotherapy,the structure and function of tumor cells evolve,which can resist multiple drugs with different mechanisms of action and"pump out"intracellular drugs?multi-drug resistance?.Subsequently,multi-drug resistant cells quickly developed into the main component of breast cancer,leading to failure of chemotherapy and tumor recurrence.Therefore,how to achieve the targeted release of anti-tumor drugs and inhibit the"drug resistance"of tumor cells has aroused the common concern of researchers.Therefore,the use of specific drug carriers to build a biofunctional drug delivery system is expected to achieve the targeted delivery of anti-tumor drugs and release within tumor cells,and effectively inhibit the"drug resistance"of tumor cells,which has attracted extensive attention from researchers.Due to its good biocompatibility,excellent loading capacity and unique physical and chemical properties,mesoporous silicon and iron-based nanomaterials have been widely developed as a drug delivery system for anti-tumor drugs.This kind of nano-drug delivery system can enhance the penetration and retention effect?EPR?in tumor site,and realize the enrichment and accumulation of loaded drug in tumor tissue.At the same time,the drug delivery system can also regulate the drug encapsulation efficiency according to clinical needs and modify the targeted molecules on the surface to improve the phagocytic efficiency of tumor cells,thus reducing the toxic and side effects of chemotherapy drugs on normal tissues.In addition,iron-based nanomaterials have unique properties such as photothermal and magnetothermal,and also have curative effects such as tumor hyperthermia and radiotherapy.However,iron-based/silicon-based drug delivery systems often develop drug resistance and heat resistance in tumor chemotherapy and hyperthermia.At the same time,the hypoxic environment of tumor tissue itself also reduced the efficacy of chemotherapy and radiotherapy.Therefore,the development of new drug delivery system that can overcome the obstacles of tumor treatment has very urgent clinical needs and practical significance.To sum up,based on mesoporous silicon and iron-based nanomaterials,this paper designed and synthesized several new nano-drug delivery systems and biofunctionalized their surfaces,in an effort to establish new ideas to curb tumor treatment obstacles,and evaluated their corresponding tumor inhibition efficacy in vivo and in vitro,respectively.The main research contents and results of this paper are as follows:?1?Construction of reduction-responsive tumor-targeted hollow mesoporous silicon nano-drug delivery system and evaluation of anti-tumor effect.In order to improve the efficiency of chemotherapy drug delivery,we choose hollow mesoporous silica as a drug carrier,by reducing sensitivity of disulfide bond to transferrin?Tf?modification to the surface of mesoporous silica,the transferrin as a block,stop drug leakage from mesoporous,and can be used as a tumor targeting molecules,improve the efficiency of tumor cells of nanoparticles.Related experimental results prove that we have successfully prepared reduction-responsive tumor-targeted hollow mesoporous silicon nano-drug delivery system?HMSNs-S-S-Tf@DOX?.The drug release behavior of the nanosystem was tested and the GSH-triggered drug release characteristics of the nanosystem were demonstrated.In vitro tumor cell phagocytosis experiments,in vivo biological distribution of nanoparticles and in vivo imaging experiments in mice confirmed that transferrin endowed this nanosystem with tumor targeting ability.Further,we carried out in vitro apoptosis analysis experiments on HMSNs-S-S-Tf@DOX system at the cell level,including laser confocal,cell flow and cell activity?MTT?.The relevant results showed that HMSNs-S-S-Tf@DOX system had better apoptosis promoting effect,indicating that the system had higher drug delivery efficiency.Finally,we evaluated the anti-tumor effect of HMSNS-S-TF-DOX on tumor-bearing mice,and the results showed that the drug delivery efficiency of HMSNs-S-S-Tf@DOX was higher than that of pure drugs,and the toxic and side effects of DOX were effectively reduced at the same time.In addition,the results of relevant in vivo experiments also showed that HMSNs-S-S-Tf had good biocompatibility and safety.This study provides a promising drug delivery system for efficient and safe cancer treatment.?2?Construction of pH/alternating magnetic field dual response magnetic targeted iron oxide nano-drug delivery system and evaluation of anti-tumor effect of thermochemotherapy combined with thermochemotherapyIn order to further improve the efficacy of nano-drug chemotherapy,we constructed a pH/alternating magnetic field dual response ferric oxide compound nano-drug loading system based on the property of nano-ferric oxide magnetothermal to conduct combined hyperthermia and chemotherapy for tumors.Polypyrrole?PPy?was coated on the surface with nano-iron oxide as the core,and PEG was further modified on the surface to make the nanoparticles hydrophilic.After DOX loading,polypyrrole,due to its dual response to pH and thermal stimulation and based on the magnetothermal properties of the nano-iron oxide core,endow the whole nano-system with dual response to pH and alternating magnetic field,as well as the potential for tumor thermochemotherapy combined therapy.Relevant experiments confirmed that we successfully prepared a pH/alternating magnetic field dual response of iron oxide nano-drug carrier system?Fe₂O₃@PPy-DOX-PEG?.Tests of drug release behavior in nanosystems show that the system has pH and alternating magnetic field triggered drug release characteristics.In vivo and in vivo thermal imaging data showed that Fe₂O₃@PPY-DOX-PEG nanosystems could generate heat and provide hyperthermia for tumors under alternating magnetic field conditions.In vitro apoptosis assays at the cell level?laser confocal,trypan blue staining,cell flow,MTT cell activity assay?showed that the combined therapy of hyperthermia and chemotherapy was significantly more effective than chemotherapy alone.Finally,we evaluated the in vivo antitumor effect of Fe₂O₃@PPy-DOX-PEG in tumor-bearing mice.The results showed that the tumor inhibition effect of combined treatment was significantly higher than that of chemotherapy or hyperthermia alone,and Fe₂O₃@PPY-DOX-PEG showed good biocompatibility and safety in vivo.?3?Construction of a reduction-responsive tumor targeted ferric oxide nanoparticles drug delivery system and evaluation of the efficacy of oxygen-sensitized tumor chemotherapyIn order to overcome the chemotherapeutic resistance induced by tumor hypoxic microenvironment,we prepared reduced responsive iron oxide nano-drug carriers with oxygen transport capacity.Porous hollow iron oxide nanoparticles were used as the substrate to load perfluorinated carbon?PFC?,which could carry oxygen,into the cavity of iron oxide.The surface was modified with a amphiphilic polymer containing lactose acid?LA??LA-PEG-S-S-C18PMH?.The hydrophobic chemotherapy drug etoposide?EP?was loaded in the hydrophobic area.The relevant characterization means confirmed that we successfully prepared reduced responsive tumor-targeted iron oxides nano-drug delivery system?PHMNP-S-S-PEG-LA@PFC?O₂?/EP?.The oxygen release experiment in solution confirmed that PHMNP-S-S-PEG-LA@PFC?O₂?/EP nanosystem has a high oxygen load and a good oxygen release capacity.At the cell level in vitro,western bolting was used to prove that the oxygen carrying nano-system could effectively relieve the anoxic state of cells,indicating its good oxygen transport capacity.At the same time,through confocal laser,cell flow and MTT cell activity detection,we found that PHMNP-S-S-PEG-LA@PFC?O₂?/EP can effectively inhibit hypoxia-induced cell drug resistance and significantly improve the performance of chemotherapy under hypoxia.Finally,in vivo experiments,we used photoacoustic imaging and intra-tumor oxygen partial pressure detection to prove that the oxygen carrying nano-system can efficiently transport oxygen to the tumor site.In addition,we evaluated the in vivo anti-tumor effect of PHMNP-S-S-PEG-LA@PFC?O₂?/EP in tumor-bearing mice,and the results showed that,compared with simple chemotherapy,the combination of oxygen transport and chemotherapy had a more significant effect in eliminating tumor and curbing hypoxic drug resistance,which was expected to be further used for clinical transformation.?4?Construction of a reduction-responsive tumor-targeting Prussian blue nano-drug delivery system and evaluation of the combined anti-tumor effects of starvation and photothermal therapyIn order to curb the thermal resistance of cells during photothermal process and further optimize the tumor inhibition effect of photothermal,we successfully constructed a reductive responsive tumor photothermal Prussian blue nano-drug system with tumor hunger ability.The glucose oxidase?GOx?was loaded into the porous hollow Prussian blue nanoparticles?PHPBN?,and then hyaluronic acid was introduced to block the glucose oxidase to prepare the multifunctional Prussian blue nano-drug carrier?PHPBN-S-S-HA-PEG@GOx?.Relevant characterization experiments confirmed that we successfully constructed PHPBN-S-S-HA-PEG@GOx.The in vitro drug release behavior experiment of the nanosystem proves that the system possesses the GOx release property triggered by GSH.The in vitro solution pH and H₂O₂concentration tests showed that the nanosystem had a good glucose consumption capacity.Cell level ATP assay further confirmed that PHPBN-S-S-HA-PEG@GOx has a significant hunger effect.The results of western bloting at the cell level and animal level showed that nanocells could effectively inhibit the expression of HSPs and disrupt the thermal resistance of tumors.Finally,we use a tumor-burdened mice to PHPBNs-S-S-HA-PEG@GOx on the in vivo antitumor effect evaluation,the results show that the system has a good effect of tumor hunger,and hunger with thermal therapy can effectively break through the thermal resistance of the tumor and the tumor sensitizing effect of field,the nanometer system for combination therapy collapse has guiding significance for tumor treatment of bottleneck.