| Doxorubicin is often used in chemotherapy for prostate cancer.When used alone,it can cause toxic side effects such as myocardial lesions and bone marrow suppression due to its poor targeting ability to tumor tissues.In order to improve its therapeutic effect,doxorubicin is often used in combination with other cancer treatment methods.Photothermal therapy(PTT)can increase the temperature of the tumor site,which increase the sensitivity of tumor cells to drugs and improve the efficacy of chemotherapy drugs.Reduced graphene oxide,as a photothermal material,can simultaneously carry benzene-containing chemotherapeutic drugs,which can be used as a paltform for chemotherapy and photothermal therapy.In order to improve its tumor targeting ability,a novel photosensitive biomimetic tumor targeting nano drug delivery system was constructed,macrophages with inflammatory and tumor tatgeting abilities were used as carriers to transport reduced graphene oxide(PEG-BPEI-rGO),DOX was used as a model drug.Its anti-prostate cancer effects in vitro and in vivo were studied.In the first part,BPEI-GO was obtained by modifying BPEI on the surface of graphene oxide by covalent bond connection.BPEI-rGO was obtained by hydrazine hydrazine reduction.In order to improve its water solubility and stability,PEG was covalently bonded to BPEI-rGO(PEG-BPEI-rGO).We verified the structure and morphology of PEG-BPEI-rGO by FI-IR,UV,Raman,DLS,AFM and other characterization methods.Doxorubicin(DOX)was used as a model drug and loaded onto the surface of PEG-BPEI-rGO in a?-?conjugate manner.The drug loading capacity of PEG-BPEI-rGO was 61.9%,and the drug loading efficiency was 30.9%.The modified reduced graphene oxide exhibited not only excellent photothermal conversion efficiency,but also significantly improved biocompatibility and water solubility.The photothermal conversion efficiency of PEG-BPEI-rGO was investigated by a thermal infrared camera.When the concentration of PEG-BPEI-rGO was 50?g/ml,the temperature could be increased to 57.8?after 5 min laser irradiation.In vitro drug release studies showed that NIR irradiation could accelerate the release rate of loaded drugs in a NIR-controlled way.In the second part,we used a murine macrophage-like cell line,RAW264.7,to construct a cell-mediated drug delivery system.Drug-loaded macrophages(MAs-DOX/PEG-BPEI-rGO)were prepared by co-incubating DOX/PEG-BPEI-rGO with macrophages.The drug loading ability of the system was 20?g DOX/10~6 cells.We examined the inflammatory tropism and tumor tropism of macrophages in vitro by transwell experiments.Under the combined action of inflammatory factors and tumor chemokines,macrophages had remarkable tumor chemotaxis ability,and after drug loading,the tumor chemotaxis ability of macrophages had not been significantly affected,which provided a guarantee for macrophages as tumor targeting carriers.We investigated the drug release bahavior and photothermal effects of MAs-DOX/PEG-BPEI-rGO in vitro,results showed that it had obvious photothermal effect and could release the loaded drug in a NIR-controlled way.The in vitro tumor suppressive effect of MAS-DOX/PEG-BPEI-rGO was investigated by CCK-8.After NIR irradiation,MAS-DOX/PEG-BPEI-rGO showed stronger antitumor effect than free DOX,indicating that the photothermal-chemo therapy can effectively inhibit tumor growth.In the third part,we established a mouse prostate cancer model to investigate the tumor targeting ability of drug-loaded macrophages in vivo.The photothermal effect of MAs-DOX/PEG-BPEI-rGO in vivo was investigated by thermal infrared camera.Antitumor effect and safety in the body were also investigated.We used the near-infrared fluorescent dye DIR to stain macrophage membranes and investigated the distribution of macrophages in tumor-bearing mice.The fluorescence signal of tumor sites increased within 24 hours,indicating that drug-loaded macrophages had significant tumor targeting ability.We used a thermal infrared camera to examine the temperature change of the tumor site after NIR irradiation.24 hours after the MAs-DOX/PEG-BPEI-rGO was injected into the mouse at a dose of 2.5×10~8 cells/kg,the temperature of the tumor site can be raised to46.3?with obvious photothermal effect.Tumor growth inhibition experiments show that doxorubicin combined with photothermiotherapy can effectively inhibit tumors growth,and the combined application of photothermal-chemo therapy has a synergistic effect,which produces better tumor suppression than single chemotherapy drugs or single photothermiotherapy.Changes of body weight during the treatment were used as an indicator of the safety,the drug delivery system we established had no systemic side effects.This research developed a biomimetic NIR-triggered drug delivery system which based on reduced graphene oxide and macrophages,this drug delivery system opened up a new therapeutic strategy for prostate cancer. |
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