Construction Of Nano-Delivery System Based On “Tumor-Derived Exosomes-Erythrocyte” For Tumor Combined Therapy

Breast cancer is an important malignant tumor that endangers women’s health.Chemotherapy is an important means to treat breast cancer.Anthracyclines are the cornerstones of chemotherapy for breast cancer and have obvious toxic and side effects.In recent years,the application of drug carriers based on nanotechnology has improved the related problems,indicating the key role of nanocarriers in improving the efficacy of chemotherapy and reducing the toxic and side effects.As exogenous substances,the existing nano-carriers cannot adapt to the physiological microenvironment in the body,and are easy to be recognized and cleared by the immune system,so it is difficult to achieve the ideal therapeutic effect.Therefore,it is the core goal of the development of nanotechnology to obtain drug carriers that match the physiological microenvironment and tumor types by using natural endogenous substances in the body.The realization of this goal will help to improve the therapeutic effect of tumor,which has important theoretical significance and practical value.Biomimetic nano-delivery system has a good application prospect.Exosomes have unique advantages as natural endogenous carriers at the nanometer level.Among them,tumor-derived exosomes have attracted much attention due to their homing effect,but their application is characterized by poor safety,short systemic circulation time and low drug load.In order to solve the above problems,the natural modification of tumor exosomes with autologous red blood cells was carried out in this paper through membrane fusion technology.1.Synthesis and Characterization of TREV biomimetic nanovesicles.We constructed a series of biomimetic nanovesicles by fusing exosomes membranes with autologous erythrocyte membrane using membrane-fusion method.The typical morphological structure of TREV was observed.TREV with uniform particle size and controllable size were constructed precisely and controllably to achieve a high coordination of safety,stability,targeting and long circulation.2.Synthesis and Characterization of TRMDI nanoparticles.On this basis,the bionic nano delivery system was designed to realize multifunctional assembly of components such as nano vesicles,mesoporous silicon particles,chemotherapeutic drugs and photosensitizers.The biomimetic visualized drug delivery system after assembly possesses the natural properties of tumor exosomes and erythrocyte membranes,realizing the long-term circulation and accurate delivery in the delivery process.Moreover,it has the property of multifunctional particles,realizing the efficient delivery of drugs,the visual monitoring of the treatment process and the coordination of combined therapy.3.Combination therapy effects of TRMDI in vitro.The results showed that under the irradiation of 808 nm near-infrared light,TRMDI had a significant photothermal effect and photodynamic therapy,which was significantly higher than that of the free ICG water dispersion solution;TRMDI had a pH/photothermal dual response drug release performance.Under the irradiation of near-infrared light,the release rate of TRMDI increased significantly.The release rate of TRMDI under the condition of pH6.5 was 65.8%;while under the condition of pH 7.4,the release rate of TRMDI was39.7%;TRMDI had a synergistic inhibitory effect on the proliferation,invasion and migration of 4T1 cells Through the expression of activated caspase3/9,it activated the apoptosis pathway.4.Combination therapy effects of TRMDI in vivo.The results found that the coating of TREV significantly increased the targeting ability and retention time of the TRMDI delivery system to tumor tissues,and it accumulated significantly at the tumor site within 48 hours;the fluorescence of ICG in the near-infrared band allowed TRMDI to be used for in vivo display: tracing and tumor imaging;under the stimulation of near-infrared light,TRMDI can be released in response to the drug at the tumor site;compared with the control group,TRMDI had a significant ablation effect on tumors because it can significantly inhibit the growth of tumors in situ and the inhibition rate increased to 90.2%.The survival period of the mice extended from28 days to 52 days;the main tissues and organs had no obvious pathological changes after the administration,the blood routine indicators were normal,there was no obvious rejection reaction and liver and kidney function damage,with good biocompatibility and safety.In summary,we have successfully constructed a series of biomimetic nanovesicles by fusing exosomes membranes with autologous erythrocyte membrane using membrane-fusion method.On this basis,we design a synergetic nano-delivery system for tumor therapy by assembling biomimetic nanovesicles,the carrier particles(MSNs),chemotherapeutic drugs(DOX)and photosensitizer(ICG),achieving long circulation,homotypic targeting,visualized therapy and combined therapy.Based on the homologous tumor model,the efficacy of this system was extensively studied by toxicity test in vitro and in vivo.Our study clearly demonstrates that exosome-biomimetic nanoparticles can be used in combined therapy,and this approach provide a new idea for developing natural drug carriers to improve the efficacy of anticancer therapy.This study will be of great significance to expand ideas for the drug delivery system.