| The treatment of cancer has been a hot topic for a long time.Many treatments have been developed during the past decades included surgery,chemotherapy,radiation therapy,and immunotherapy etc..With the advancement of sciences and technologies,new treatment methods such as hyperthermia,photodynamic therapy and cryo-therapy have emerged.Although there are many available therapeutic approaches,the limitations still remain: high toxicity,serious side effects,high cost and long treatment cycles etc..Combination therapy has become a common method for tumor treatment in clinical practice to amplify the therapeutic effect and minimize the side effects.The combination of hyperthermia and chemotherapy,especially when in combination near-infrared(NIR)photothermal therapy with chemotherapy has become increasingly popular.In the past,gold nanoparticles was used as photothermal agent despite its poor biocompatibility and slow clearance which has limited its clinical applications.In view of this,indocyanine green(ICG)were used as a substitute for gold nanoparticles,although it is not stable in physiological environment and inclined to rapid clearance.Therefore,successful ICG based NIR photothermal-chemotherapy would require the development of a drug delivery system which can stabilize ICG with good biocompatibility,biodegradability and targeting ability when ICG and chemotherapy drugs are loaded.A novel amphiphilic copolymer polysulfide-b-poly(N-isopropylacrylamide-co-N,N-dimethylacrylamide)(PPS-b-P(NIPAm-co-DMAA))was designed and synthesized in this study.The polymer could self-assemble in aqueous solution and form shell-core nanomicelles.The shell is responsive to temperature and the core is responsive to oxidants.Through microscopic observation the nanomicelles were showed as spherical structures and the particle size was about 69.5 nm.After ICG and doxorubicin(DOX)were co-encapsulated in the nanomicelles,the drug-loaded micelles showed higher photothermal efficiency than free ICG under the NIR irradiation at 808 nm.Under higher temperature above its LCST,P(NIPAm-co-DMAA)chains would collapse in water and resulted in a hydrophilic to hydrophobic transition on it surface,leading to the enhanced uptake of the micelles by A549 cancer cells.The singlet oxygen produced from ICG under irradiation could also oxidize PPS core and release encapsulated DOX.The cell viability was 43% and 38% by photothermal therapy or chemotherapy alone in in vitro experiments,respectively.However the viability of tumor cells was lowered to 8% by ICG and DOX co-loaded micelles.After such results were obtained,we investigated the anti-tumor effects of the micelles in vivo.The tumor was irradiated with NIR at 808 nm after 5 minutes and its temperature increased to 55°C.Furthermore,through the living fluorescent imaging system,the accumulation of the co-loaded micelles at the tumor site was observed and recorded.After administration of the drug loaded micelles on xeno-grafted A549 tumor nude mice and applying NIR irradiation,the tumors on mice of ICG/DOX group shrank and disappeared after 16 days,compared to the uninhibited tumor growth in other groups.Finally,there were no significant differences among heart,liver,spleen,lung and kidney samples collected in all groups after H&E staining,which demonstrated the relative safe profiles of photothermo-chemotherapy,although the changes in tumor tissue were consistent with the result in previous in vivo anti-tumor efficacy experiment.Our experimental results showed that the dual-responsive nanomicelles designed in this study,after being co-loaded with photothermal agent(ICG)and chemical drug(DOX),demonstrated better anti-tumor effect than monotherapy both in vitro and in vivo and achieved combinational photothermo-chemotherapy effect. |
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