The Preparation And Evaluation Of Tumor Active Targeting NIR Triggered Drug Delivery System

Drug delivery systems is always facing with the challenge of drug release issues,while near-infrared-responsive temperature-sensitive drug delivery systems can achieve rapidly drug release.In the study,a tumor active targeting with NIR-triggered rapidly drug release drug delivery system was constructed to achieve highly effective and low toxicity chemo-phototherapy.In the study,Acrylamide(AAm)and Acrylonit(AN)were polymerized to form a temperature-sensitive polymer poly(Acrylamide-co-acrylonitrile)(p(AAm-co-AN))via radical polymerization.According to the relationship between radical polymerization initiator,feed ratio,molecular weight and the upper critical solution temperature of the polymer,chose initiator azobisisobutyronitrile(AIBN)as 1%wt,the molar ratio of AAm and AN as 16:9 and the reaction time as 24 h to obtain 20.5 k Da molecular weight and45℃ upper critical dissolution temperature of poly(acrylamide-acrylonitrile)p(AAm-co-AN).Hyaluronic acid(HA)as the hydrophilic and tumor“guider”,was conjugated with poly(acrylamide-co-acrylonitrile)to produce tumor targeted and temperature-responsive polymeric nanocarriers Hyaluronicacid-poly(acrylamide-co-acrylonitrile)(HA-P).HA-P could self-aggregated to form micelle structure in aqueous.Pyrene fluorescence method was used to determine the critical micelles concentrations(CMC),which was 72.2μg/m L.The particle size was 250.6±2.8 nm and the surface potential was-28.2±0.3 m V.When the ambient temperature≥45℃,the particle size of HA-P micelles decreased to under 10 nm,which indicated the micellar structure collapsed.The micellar structure was stable at room temperature under transmission electron microscope,while micellar structure collapsed at ambient temperature≥45℃.Doxorubicin was used as a chemotherapy model drug,Indocyanine green was used as a photosensitizer.The DOX&ICG co-loaded nanoparticles(HA-P/DOX&ICG)were obtained via a dialysis method.The particle size of HA-P/DOX&ICG nanoparticles were217.5±0.9 nm and the surface potential were-24.1±1.4 m V.When the ambient temperature≥45℃,the particle size of HA-P/DOX&ICG nanoparticles decreased to under 10 nm,which indicated the nanoparticle structure collapsed.At NIR irradiation(808 nm,1 W/cm~2,5min),when ICG concentration was 10.0μg/m L,the temperature of HA-P/HC&ICG increased 23.7℃,the photothermal conversion efficiency was slightly higher than free ICG(22.5℃).The temperature-dependent and NIR triggered of drug release evaluated via the dialysis method.HA-P/DOX&ICG nanoparticles showed sensitively drug release at varies pH conditions when the ambient temperature was 45℃and under near-infrared condition.Human breast adenocarcinoma cells(MCF-7)were used as model cells.Mediated by CD44 receptors on the surface of cell,MCF-7 increased the cellular uptake of HA-P/DOX&ICG nanoparticles.Replace DOX by Nile red(NR),HA-P/NR&ICG was obtained.NIR-laser irradiation could effectively trigger more drug release from HA-P/NR&ICG in cell.After NIR irradiation,an extremely improved cytotoxicity of HA-P/DOX&ICG(IC50 decreased from 3.78 to 1.46μg/m L)was observed.SOSG was used to verify ROS generation ability of MCF-7,under NIR-laser irradiation,the Chemo-phototherapy groupHA-P/DOX&ICG significantly increased ROS generation levels compared to single chemotherapy HA-P/DOX and single phototherapy HA-P/ICG.The apoptosis-promoting ability of each preparation was investigated via flow cytometry,and HA-P/DOX&ICG with NIR group had the highest rate of late apoptosis(55.41%).The MCF-7 xenografted tumor mice model was established.HA-P/DOX&ICG nanoparticles could actively accumulate at the tumor site via in vivo near-infrared fluorescence imaging.Compared with the negative control,the tumor inhibition rates of the HA-P/DOX&ICG groups with or without NIR irradiation were 95.9%and 61.8%,respectively.Therefore,our study showed that the NIR triggered and tumor active targeted drug delivery system HA-P/DOX&ICG could actively target at the tumor site which reduce the toxic side effects of the DOX.When ambient temperature≥upper critical dissolution temperature,the physical characteristics of temperature-responsive polymer changed,lead to nanoparticle structure collapsed and improve the release of DOX,which significantly improve chemo-phototherapy efficiency and enhance antitumor efficacy in vivo,is a potential treatment for antitumor.