Preparation Of Multifunctional Theranostic Nanoprobes For Treatment Of Orthotopic Colorectal Cancer

Colorectal cancer is one of the most common malignant tumors with high mortality and morbidity in the clinical,which have a poor impact on human health.At present,the standard clinical treatment methods are surgery and chemotherapy.But the prognosis of colorectal cancer is dissatisfactory.Therefore,it is necessary to find other ways to improve the efficiency of colorectal cancer treatment.More and more multifunctional nanoplatforms for diagnosis and treatment have been developed.In this system,with the design of diagnosis and treatment strategies for colorectal cancer,guided by CT/ fluorescence imaging,the multimodal therapy of colorectal cancer was realized.The main research contents were as follows:(1)An enteric-soluble granules for oral administration with progressively targeting and p H/US response were synthesized.The gold nanoparticle coated with mesoporous silicon loaded with chlorin(Ce6)and doxorubicin(DOX),then coated with phospholipid modified with folic acid(FA)for ultrasonic response,and finally coated with an enteric-soluble carboxymethyl chitosan(CMC),the enteric-soluble granules were synthesized.The entericsoluble granules were very stable in simulated gastric juice(p H=2),while CMC gradually disintegrated in simulated intestinal juice(p H=6.5)to release GMCDS-FA nanoprobes.In vitro experiments showed that GMCDS-FA nanoprobes had excellent ability of controlled release under ultrasound stimulating and ability of CT targeting imaging for colorectal tumor site.The cell survival rate of the combined chemotherapy and photodynamic therapy group was 45.2±1.8% significantly higher than that of the single treatment group.During the experimental period,after 20 days in the experimental group,the number and size of colorectal tumors were significantly lower than those in the other control groups,indicating that the enteric-soluble granules realized excellent therapeutic effects in chemophotodynamic combined therapy.Therefore,this nanoprobe had great potential in the treatment of orthotopic colorectal cancer.(2)A self-generated oxygen biomimic nanoplatform based on hybrid membrane composed of neutrophil membrane and red blood cell membrane was prepared.The nanoplatform was an organometallic framework(ZIF-8)loading Ce6 coated with hybrid membrane composed of ascorbyl palmitate(PA),neutrophil(Nm)and red blood cell membrane(Rm).The experimental results demonstrated that the lymphocyte functionrelated molecule(LFA-1)expressed on the surface of Nm could target inflammation of the tumor site of enteritis colorectal cancer,and could reduce the chemotaxis of endogenous neutrophils to the tumor to avoid the infiltration of neutrophils at the tumor site for blocking immune escape.In vitro experiments showed that Rm and PA in hybrid membrane formed a self-generating oxygen system and had good stability in oxygen production.In vivo experiments demonstrated that the nanoplatform could improve the hypoxia in the tumor site,reprogram the immunosuppressive tumor microenvironment caused by hypoxia,and enhance the immuno/oxygen-enhanced sonodynamic synergistic therapy.This work provided a new idea for the targeting therapy of orthotopic colorectal cancer.(3)A nanoplatform based on M1 macrophage-derived exosome(M1 exo)was constructed to realize reprogrammed immune microenvironment and NO gas-enhanced photodynamic therapy.Upconversion materials(UCNPs)loaded with Ce6 adsorped onto the surface of M1 exo,finally the nanoprobe M1 UC was synthesized.The experimental results showed that UCNPs could realize photodynamic therapy under near-infrared light excitation with 808 nm excitation since emission wavelength of UCNPs coincided with the absorption wavelength of Ce6.Cell experiments showed that M1 UC could reprogram M2 macrophages to repolarize into M1 macrophages and produce NO gas.After 20 days of experiment,there were almost no proliferating tumor cells in the synergistic treatment group of mice with orthotopic colorectal cancer,indicating that the nanoprobe had realized significant effect in immune/gas/photodynamic three-mode synergistic therapy under the808 nm excitation.This nanoprobe provided an effective strategy for the treatment of deep tumors such as orthotopic colorectal cancer.Above all,there works developed a variety of theranostic strategies for orthotopic colorectal cancer by constructing multifunctional nanoplatforms for multiple diagnosis and treatment,provided a new way for the treatment of orthotopic colorectal cancer in clinical.