Biomimetic Dual-drug Delivery Nanosystem For Chemo/Photothermal Therapy

In recent years,the nanosystem loaded chemotherapeutic drugs and photothermal(PTT)agents to achieve better anti-tumor efficacy has been a crucial focus on tumor treatment.However,intense local hyperthermia usually leads to secondary or direct cell necrosis of surrounding normal cells,triggering an inflammatory response in vivo.Meanwhile,the inflammation is usually associated with various side effects,including tissue damage,tumor resistance,or cancer recurrence.In this paper,based on the study of photo/chemotherapy of Prussian blue(PB)and gamabufotalin(CS-6),assisted with anti-inflammation and sensitization of indomethacin,we constructed a biomimetic dual-drug delivery nanosystem loaded with CS-6 and IND.The nanosystem accurately located the tumor tissue through the long circulation in vivo and good homologous targeting ability endowed by the biomimetic hybrid membrane.Based on endogenous specific substance glutathione(GSH)in tumor microenvironment,IND was released to sensitize tumor cells and relieve inflammation triggered by PTT through COX-2/PGE2 pathway regulation.In this way,it could maximize the efficacy of photo/chemotherapy based on CS-6 and Prussian Blue(PB).Following are the main research contents:1.Development of biomimetic dual-drug delivery nanosystem and performance research in vitroCubic mesoporous PB nanoparticles were synthesized by hydrothermal method.After the chemotherapeutic drug CS-6 was physically loaded,a layer of polydopamine(PDA)was coated on the surface.Through chemical modification,a linking agent containing disulfide bonds is used to connect IND and PDA.Finally,the biomimetic membrane(RBC-Hela e M)coating technology was used for bio-camouflage,and a biomimetic dual drug-loaded nano-delivery system(PCDI@M)co-loaded with CS-6 and IND was constructed.Transmission electron microscopy,Zeta particle size,Fourier infrared transform spectroscopy,SDS-PAGE and other techniques characterize the successful construction of PCDI@M.In vitro photothermal experiments show that the delivery system can quickly heat up to nearly28.4 ℃ after being irradiated by the near-infrared laser.And after cyclic radiation,the temperature increase range is still about 30 °C,which has a good and stable photothermal effect.In vitro biocompatibility experiments showed that compared with PCDI,the uptake of PCDI@M in macrophages is reduced by about 50 %,and the hemolysis and coagulation rate are all lower than 5 %,which has strong immune evasion ability and blood safety.2.Biomimetic dual-drug delivery nanosystem for photo/chemotherapy to cervical cancerIn the cell experiment,the combination of IND and low-dose CS-6(50 n M)significantly alleviated the inflammatory response and reduced the secretion of inflammatory factors TNF-α,IL-6 and IL-1β.In addition,based on the ability of PGE2 to promote the proliferation of Hela cells through the anti-apoptotic protein Bcl-2,the cytotoxicity of CS-6/IND combination therapy was increased to more than50 %,which was higher than the cytotoxicity of single-agent CS-6(25 %).More importantly,the biomimetic dual drug-loaded nano-delivery system PCDI@M combined with photothermal therapy,which is co-loaded with both,maintains cytotoxicity above 85 %.At the same time,it reduces the levels of inflammatory factors TNF-α,IL-6 and IL-1β to near normal levels.In the in vivo anti-tumor experiment,the in vivo fluorescence imaging system showed that the blood half-life of PCDI@M was significantly better than that of PCDI,which was extended by nearly 1.5 times(10.8 h VS 4.4 h),and the cumulative amount of tumor increased to more than 2 times.After the treatment,the tumor inhibition rate(TGI)of the mice was as high as 95.6 %.There was no recurrence or death within 30 days,and the survival time was prolonged.At the same time,there were no abnormalities in biochemical indicators or pathological sections.