Stimuli-responsive Multifunctional Liposomes For Multimodal Synergistic Tumor Therapy

Generally,single-mode tumor treatment is difficult to achieve satisfactory therapeutic effects.Multimodal combination therapy can achieve synergistic antitumor effects by different tumor inhibition mechanisms,and significantly improve efficacy.In addition,the targeted delivery and controlled release of drugs at tumor sites remain a difficult problem for high-efficient and low-toxic tumor treatment.In order to solve the above problem,we prepared the stimuli-responsive multifunctional liposomes,which could induce a responsive drug release by external stimuli or tumor microenvironment,and achieve the multimodal synergistic antitumor effect.1.The folate modified DSPE-PEG-FA,cholesterol,and DPPC were chosen as the raw materials.A folate targeting/near infrared light responsive multifunctional liposome system(Cy/Ce6/CO2-FA/Lip)was prepared by thin film dispersion and NH4HCO3 gradient method.Photothermal agent Cypate and photosensitizer Ce6 were co-loaded in the phospholipid bilayer.The liposomes were spherical,uniform in size,and had a good photothermal effect.Cy/Ce6/CO2-FA/Lip exhibited the strongest singlet oxygen generation ability after irradiation at 785/660 nm.In vitro release results showed that CO2 bubbles were generated due to the decomposition of NH4HCO3 at 42℃,which could trigger the rapid release of drugs.Cellular uptake and in vivo imaging indicated that the liposomes had the properties of fluorescent imaging and targeting effect.In vivo and vitro antitumor activity implied that CO2 bubble generation,folate targeting and sequential laser irradiation at 785/660 nm could significantly enhance the antitumor effect and achieve PTT/PDT synergistic effect.2.The redox responsive multifunctional liposomes(Ce6-Lip-S-S-Pt/Los)were prepared with the cisplatin prodrug DSPE-S-S-Pt,HSPC,and cholesterol by thin-film hydration and calcium acetate gradient method.In the liposomes,Ce6 was loaded in the phosphatide bilayer,cisplatin prodrug was modified on the surface,and losartan(Los)was encapsulated in the aqueous phase.The liposomes had a uniform size and high encapsulation efficiency.The liposomes exhibited a good stability and singlet oxygen generation ability.In vitro release showed that the release of Pt had a redox response in the presence of hematoxylin.Cellular uptake and in vivo imaging implied that the Ce6-Lip-S-S-Pt/Los could enhance the enrichment of drugs in tumor cells and tumor tissues.In vitro and in vivo antitumor activity demostrated that Ce6-Lip-S-SPt/Los had a good antitumor effect due to the redox responsive release of DSPE-S-S-Pt and the enhanced penetration effect of losartan,improving chemotherapy/PDT synergistic antitumor efficacy.In summary,the stimuli-responsive multifunctional liposomes had the capabilities of targeting tumor tissue and NIR/tumor micro-environment responsive drug release,which can improve the drug enrichment in tumor tissues,and achieve multimode synergistic antitumor effect.