Preparation Of Light-responsive Nano Drug Delivery System And Study On Their Antitumor Effect

Due to the high morbidity and high mortality,cancer has been threatening human's life and health seriously.Stimuli-responsive nano drug delivery system,as a new delivery carrier of chemotherapeutic drugs,has attracted extensive attention of researchers.Among them,because of the strong tissue penetration ability of near-infrared?NIR?light,the NIR light-responsive nano drug delivery system has shown a good application prospect in the field of cancer treatment.In this study,NIR light was used as trigger medium,liposome?Lip?and graphene oxide?GO?were selected as drug carriers,gold nano-shell?AuNS?and indocyanine green?ICG?were used as photothermal converters and photosensitizers.Four different light-responsive nano drug delivery systems were constructed and the relevant response mechanisms were explored.The specific contents are as follows:?1?By the ethanol injection method,the liposome encapsulated with natural anti-tumor active ingredient Wedelolactone?Wed?was prepared,and it's named Wed-Lip.The gold nano-shell coated Wed-Lip?AuNS-Wed-Lip?was synthesized by seed growth method.Based on the surface plasmon resonance?SPR?effect of gold nanoparticles,the AuNS showed characteristic absorption peaks in NIR region.Under 808 nm NIR light irradiation,AuNS converted light energy to heat effectively,which promoted the rapid increase of local temperature.On the one hand,the system achieved NIR light-responsive photothermal treatment?PTT?;on the other hand,hyperthermia led to phase transformation of the lipid membrane structure of liposome,and enhanced fluidity and permeability of the phospholipid membrane.Under NIR light irradiation,the drug release amount reached up to 97.34%in 8 hours,which realized NIR-responsive drug-controlled release.The antitumor effect of AuNS-Wed-Lip was explored by cell experiment in vitro and animal experiment in vivo.The results showed that AuNS-Wed-Lip had a good anti-tumor effect under NIR light radiation.?2?A novel NIR light-responsive nano drug delivery system ICG-Wed-Lip was successfully obtained by co-encapsulating ICG and Wed into liposome.As a NIR absorption dye,ICG shows significant characteristic absorption peaks in NIR region,which endows ICG-Wed-Lip with excellent photothermal conversion performance.The solution temperature could rise to 43?after 12 minutes of NIR light irradiation,which not only realized PTT treatment,but also promoted the phase transition of phospholipid membrane and achieved NIR light-responsive drug release.After 8 hours of NIR light irradiation,the drug release amount reached 96.74%.The result of MTT experiment showed that ICG-Wed-Lip could achieve the synergistic effect of chemotherapy and PTT under NIR light irradiation,and inhibit the viability of tumor cells by inducing apoptosis.The result of animal experiment also proved the good antitumor effect of ICG-Wed-Lip.?3?Graphene oxide?GO?was selected as a new drug carrier,and the co-loading of ICG and Wed was realized by?-?stacking and hydrophobic interaction.The light-responsive nano drug delivery system ICG-Wed-GO achieved the synergistic effect of chemotherapy,photodynamic therapy?PDT?and PTT.ICG-Wed-GO exhibited good photothermal properties under NIR light irradiation.After 10 minutes of irradiation,the temperature rose to 79.4?,which met the need of PTT treatment.At the same time,due to the increase of local temperature,the?-?stacking between Wed and GO was weakened,achieving NIR light-responsive drug-controlled release.In addition,the photothermal stability of the ICG was improved by decreasing the photoinduced ICG decomposition,due to the electron donor quenching of GO.As a photosensitizer,under NIR light irradiation,ICG at the ground singlet state can be activated to triplet state.Then the triplet state of ICG can transfer its energy to triplet oxygen and generate plenty of reactive oxygen species?ROS?,which can cause oxidative damage to tumor cells,induce apoptosis and realize PDT therapy.The synergistic effect of three treatments made ICG-Wed-GO exhibit excellent antitumor effects in vitro and in vivo,and proved its good biocompatibility and biological safety.?4?Based on the research of ICG-Wed-GO,a PDT-enhanced NIR light-responsive drug carrier DOX-ICG-GO@MnO₂ was obtained by combining MnO₂ nanoparticles with GO,and loading ICG and doxorubicin?DOX?through?-?stacking and hydrophobic interaction.The results showed that MnO₂ nanoparticles could catalyze the decomposition of H₂O₂ and produce oxygen under acidic conditions.On the one hand,the property can alleviate the hypoxia of tumor tissue;on the other hand,it can provide oxygen source for PDT treatment and improve its therapeutic effect.Under the stimulation of NIR light,the system achieved PTT treatment and drug-controlled release,due to the good photothermal properties of ICG.At the same time,MnO₂ nanoparticles catalyzed the decomposition of H₂O₂ to produce oxygen,which resulted in that ROS production was significantly increased and PDT effect was enhanced.The experiment results in vitro and in vivo proved the excellent antitumor effect.In summary,four different NIR light-responsive nano drug delivery systems were synthesized,which not only achieved light-responsive drug-controlled release,but also achieved the synergistic effect of chemotherapy,PTT therapy and PDT therapy.The light-responsive mechanisms of different drug delivery systems were explored.This work can provide theoretical basis for the application of NIR light-responsive nano drug delivery system in the field of cancer treatment.