Near-infrared Light-responsive And Mitochdra-targeted Graphene Based Photoimmuno Namocomplex For Enhanced Cancer Therpy

Phototherapy,including photodynamic therapy(PDT)and phothermal ththerapy(PTT),has attracted tremendous interest for cancer therapy owing to its advantages like noninvasive nature,negligible drug resistance,low systemic toxicity and etc.Particularly,the near-inferred(NIR)light(700-850 nm)mediated phototherpy exerted greater efficacy against deeper cancer because of its higher tissue penetration.And,mitochondria-targeted PDT triggered enhanced PDT efficiency when ROS generated in mitochondria since mitochondria had been demonstrated as an appealing subcellular target for PDT.On the other hand,phototherpy can stimulate immune responses and this phenomenon motivates a new approach by combining with immunostimulants to enhance the anti-tumor immunity.For this sake,functionalized nanocarriers are emerged as a promising platform to combine photosensitizer,immunostimulants and targeting ligands into a single system to realize the combination therapy of phototherpy and immunotherapy.Herein,a type of NIR light triggered and mitochondria-targeted nanocomplex based on graphene oxide(GO)was fabricated for the combination therapy of phtotherapy and immunotherapy.Mitochondriotropic ligand triphenylphosphonium(TPP)cations was conjugated with 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amine(polyethylene glycol(DSPE-PEG-NH2)polymer and noncovalently assembled on the surface of GO to yield a targeted carrier(denote as GT).Then,DSPE-PEG-CpG ODN conjugates and NIR photosensitizer IR820 were loaded on GT via supramolecular ?-? stacking interaction(IR 820 loading was c.a.30%).The obtained nanocomplex GT/DP-CpG/IR820 showed good biocompatibility,considerable high ability of singlet oxygen generation and photothermal effect.GT/DP-CpG/IR820 efficiently localized in mitochondria after 4 h cellular uptake as confirmed by confocal microscopic images.The in-vitro anticancer assay revealed that GT/IR820 exhibited higher cancer cell-photokilling efficiency againtst EMT-6 cancer cells compared with non-target counterpart.Also GT/DP-CpG remarkably stimulated proinflammatory factors(i.e.TNF-?,IFN-? and IL-6)towards RAW264.7 cells,but rather than anti-inflammatory factor(i.e.IL-10).Moreover,the in-vivo assays reveal that the engineered GT/DP-CpG/IR820 exhibited significantly antitumor efficacy compared with the GT/DP-CpG and GT/DP-CpG complex.And,GT/DP-CpG/IR820 had good biocompatibility as revealed by the biochemistry analysis.Thus,this thesis provides strong evidence that the GT/DP-CpG/IR820 conjugates can be utilized as efficient antitumor agents for cancer combination therapy of phoththerpy and immunotherapy.