Temperature/Redox-responsive Nanogels For Near-infrared-triggered Synergistic Thermo-chemotherapy

Nanotechnology-based drug delivery systems(NDDSs)exhibit promising therapeutic efficacy and reduced side effects in cancer therapy owing to enhanced permeability and retention(EPR)effect.NDDSs must overcome a series of physiological barriers from the intravenous injection site to the targeting site,including blood circulation,tumor accumulation,tumor penetration,internalization by cancer cells,lysosomal escape and on-demand intracellular drug release.Some smart NDDNs responding to pH,redox often encounter difficulty in circumventing all the barriers at the same time and achieve limited therapeutic efficiency.Hyperthermia is one of the therapy methods used for cancer treatment.It not only kills cancer cells directly and increases blood flow to the heated area and augments tumor vascular permeability,but also enhances the sensitivity of cancer cells to chemotherapy.In recent years,near-infrared(NIR)-induced photothermal therapy(PTT)is usually associated with chemotherapy for cancer therapy.Local hyperthermia can lead to tumor site-specific accumulation,penetration and cellular uptake of systemically administrated thermal-responsive NDDSs.In this study,temperature/redox-responsive nanogels were used to load ICG and DOX(I/D@NG)for cancer synergistic thermo-chemotherapy.We studied the blood circulation of I/D@NG,and influence of NIR on the tumor accumulation,tumor penetration,internalization by cancer cells and lysosomal escape of I/D@NG.Furthermore,the synergistic antitumor efficiency was also evaluated.The main contents and results were as following,1)Temperature/redox-sensitive nanogels were prepared based on temperature sensitive NIPAM,zwitterionic sulfobetaine methacrylate(SBMA)and hydrophilic methylallyl amine(MAA)as comonemers and disulfide bond-containing N,N'-bis(acryloyl)cystamine(BAC)as a crosslinker.I/D@NG was constructed by organic solvent evaporation method.The hydrodynamic size of I/D@NG was about 110 nm and its zeta potential was-17.2 mV at pH 7.4.TEM showed that I/D@NG was almost uniform with spherical morphology.VPTT of the nanogels was calculated to be 40.6 °C by Boltzmann fitting and corresponding differential,suggesting that the nanogels maintained swollen state(hydrophilic)in blood(37 ?,pH 7.4).Compared with free ICG/DOX,I/D@NG performed higer photothermal conversion efficiency and NIR-induced photothermal effect dramatically decreased the size of I/D@NG.Drug release behavior of I/D@NG exhibited a synergistically GSH and NIR dual-stimuli responsive DOX release.2)The pharmacokinetic behavior in SD mice showed that I/D@NG exhibited prolonged blood circulation.NIR irradiation at tumor sites significantly enhanced tumor accumulation,tumor penetration and cellular uptake of I/D@NG.Furthermore,I/D@NG could effectively escape from lysosomes by singlet oxygen-induced lysosomal disruption and DOX was then sufficiently released from the nanogels to nucleus responding to high intracellular GSH and photothermal effects.3)I/D@NG revealed a synergistic thermo-chemotherapeutic activity against HepG2 cells.The in vivo anticancer experiments showed that I/D@NG exhibited an almost tumor eradication upon NIR irradiation and the treatment process did not produce any systemic toxicity.In summary,we have successfully developed zwitterionic temperature/redox-sensitive nanogels to codeliver ICG and DOX.I/D@NG with enhanced photothermal effect exhibited in vitro synergistic photothermal and chemotherapeutic cytotoxicity.More importantly,NIR-induced hyperthermia significantly improved in vivo process of I/D@NG after systemic administration,including enhanced tumor accumulation,tumor penetration and cellular uptake.Furthermore,I/D@NG escaped from lysosomes through singlet oxygen-induced lysosomal disruption and DOX was then sufficiently released on-demand to nucleus responding to intracellular high GSH and NIR-induced photothermal effects.This NDDS not only efficiently exerted synergism of thermo-chemotherapy,but also its photothermal effect contributed to overcome a series of in vivo physiological barriers of chemotherapeutic agent,resulting in excellent antitumor effect.