Controlled Fabrication Of Hierarchical Mesoporous Silica And Black Phosphorus Nanohybrids For Targeted Synergistic Photothermal-Chemotherapy Of Cancer

With the diversified development of tumor treatment methods,the use of well-designed advanced nano drug delivery systems for multimodal coordinated treatment of tumors has become increasingly important and significant.Mesoporous silica nanoparticles(MSNs)have become a more popular nano-carrier because of its large specific surface area,controllable structure,high biocompatibility,and easy surface modification.At the same time,MSNs also have the defects that unable to support a variety of small and large guest molecules required simultaneously because of the small pore size.As a two-dimensional material,black phosphorus(BP)has high photothermal conversion efficiency and photodynamic effects in the near-infrared light region,but BP can be degraded into a safe and non-toxic phosphate in vivo,which makes it superior to other organic photothermal therapeutic agents in biological application.However,the rapid degradation and excretion of BP in vivo also limit its biological applications.This paper comprehensively considered the advantages and disadvantages of MSNs and BP,and first explored an intelligent delivery system based on hierarchical mesoporous silica(FMSN)and black phosphorus nanohybrids.The system reversed the disadvantage of rapid degradation of BP in vivo and gave the nanohybrids the characteristics of chemo-photothermal synergy in cancer.The main research contents and results are as follows:Firstly,this paper discusses the preparation methods and conditions for obtaining high yields of 150-200 nm black phosphorus nanosheets(BPNSs)and black phosphorus quantum dots(BPQDs)less than 10 nm.By exploring the conditions of ultrasonic and electrochemical exfoliation of bulk BP to prepare small-sized BP,it was found that the combined application of electrochemical and ultrasonic exfoliation is conducive to obtaining the desired BP products and improving the corresponding production rate.With the improvement of the joint exfoliation method,the yield of the ideal BP products up to 21.6%,which greatly improves the yield and efficiency of the separate exfoliation method.Secondly,in order to build an intelligent nano drug delivery system suitable for synergistic treatment of malignant tumors,a hierarchical mesoporous silica(FMSN)and black phosphorus(BP)nanohybrid with photothermal-chemotherapy effect was designed and prepared in this paper.The positive charged FMSN and negative charged BPQDs are combined by electrostatic adsorption into a FMSN@BP nanohybrids,and then modified with the target group folic acid(FA)of folate receptor which is highly expressed in the tumor site to enhance tumor targeting.Furthermore,the FMSN@BP nanohybrids exhibit good biocompatibility,high DOX loading capacity(328.3%),excellent near-infrared photothermal performance,and p H/photothermal responded drug release.And the comparison also suggests that FMSN has a stronger protective effect on the rapid degradation of BP than ordinary pore size MSNs and improves the stability of BPQDs.At last,the cell survival rate of the nanocomposites under NIR laser irradiation(26.50%)was significantly lower than the cell survival rate in the absence of NIR irradiation(45.22%).In vivo tumor suppression experiments further confirmed that the FMSN@BP-DOX-FA has a longer tumor site retention in tumor-bearing mice and shows the strongest tumor growth inhibition under NIR irradiation than other control groups.At last,the important organs of the mice were taken for H&E staining analysis,the results proved the nanohybrids did not cause other systemic toxicity to the mice.In summary,high yield BPNSs and BPQDs were prepared by combining electrochemical and ultrasonic exfoliation methods in this paper.The amino-modified and positively charged FMSN was prepared by one-step method,then the FMSN@BP nanohybrids were obtained by electrostatic adsorption,followed by FA modification and DOX loading.Therefore,a synergy system with photothermal-chemotherapy effect was constructed,and finally achieved excellent antitumor effect in synergistic antitumor therapy in vivo.