Application Of Reactive Oxygen Species-sensitive And Mitochondria-targeting Nanoparticles In Lung Cancer Imaging And Treatment

Mitochondria are critical subcellular organelle for aerobic respiration and are considered as the cellular power source.Mitochondria are also regulators of the intrinsic pathway of apoptosis,which is regarded as the major mode of cell death in cancer therapy.Also,mitochondrial dysfunction has been associated with multiple aspects of tumorigenesis and tumor progression.Mitochondria of cancer cells are different from that of normal cells.Mitochondrial membrane potential（ΔΨm）in most cancer cells is higher than that in normal cells and favors the uptake of cationic drugs and nanoparticles in carcinoma cells.One strategy for targeting mitochondria is to use the lipophilic cation.Singlet oxygen（¹O₂）,one type of reactive oxygen species（ROS）,is the principal cytotoxic agent in photodynamic therapy.Due to the short lifetime（<0.1ms）and small diffusion radius of ROS（<20 nm）in biological systems,the photosensitizer should be spatially close to the targeted site of action in photodynamic therapy.Mitochondria are key organelles for respiration and the primary source,approximately up to 90%,of cellular ROS generation.Hence,the mitochondria-targeting nanoparticles loaded with photosensitizers can perturb ROS homeostasis and further induce cell apoptosis,which can improve photodynamic therapeutic efficiency.Normal cells,with lower ROS basal stress and reserve,appear to have a higher capacity to fight against additional ROS-generating insults than cancer cells.Therefore,the elevation of ROS around tumor environment can selectively kill cancer cells.To obtain the best therapeutic effect while avoiding negative side effects,a variety of nanomaterials were developed to deliver drugs with controllable/on-demand release properties.Many controllable release methods,such as pH,redox,temperature,enzyme,and light,have been used for drug release.However,few reports have focused on the drug controlled release of ROS-responsive,especially,on near-infrared light triggered ROS induced drug controlled release.In this paper,three different new nanoparticles were prepared,with modified by ROS-sensitive linker or mitochondria-targeting small molecule.Main contents are as follows:1.Here,a new 980 n laser triggered ROS-responsive upconversion nanoparticles system was designed and prepared,which can be used in chemo-and photodynamic combination therapy for lung cancer.A thioketal linker-based ROS responsive camptothecin prodrug was prepared and the thioketal linker could be cleaved by ROS.Few reports are associated with laser triggered ROS release and the ROS can cleave the ROS-responsive thioketal linker.The upconversion nanoparticles（UCNPs）were modified by the camptothecin prodrug,photosensitizer Chlorin e6（Ce6）,and carboxyl-mPEG.Under 980 nm laser irradiation,the UCNPs system emitted a narrow emission band at 645-675 nm which was overlapped with Ce6 absorption peak.Ce6absorbed the light to produce ROS,which was used for photodynamic therapy and to cleave the thioketal linker to release camptothecin for chemotherapy.Meanwhile,Ce6absorbed the light,was used for fluorescence imaging.The release of camptothecin provided the advantage of the precisely controlled release of drug both in space and time triggered by laser.The in vivo biodistribution studies showed that the prepared nanoparticles had high orthotopic lung cancer targeting efficiency.The in vivo therapeutic results demonstrated that NCI-H460 lung cancers could be completely eliminated by combining chemo-and photodynamic therapy with 980 nm laser irradiation.2.Here,a new mitochondria-targeting ROS-sensitive blended nanomicelles platform was designed and prepared,which can be used in chemo-and photodynamic combination therapy for lung cancer.The platform was constructed for delivery of the photosensitizer Zinc phthalocyanine（ZnPc）by blending the ROS-sensitive block copolymer TL-CPT-PEG_1K-TPP with 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy（polyethylene glycol）]（DSPE-PEG）.Lipophilic cationic triphenylphosphine can go through the cell membrane and mitochondrion membrane easily,which can selectively accumulate several hundred-fold within mitochondria.The thioketal linker is ROS-responsive and camptothecin（CPT）can be released upon ROS cleavage.We also show that the ZnPc loaded in nanomicelles absorbed the 633 nm laser to produce ROS,which could be utilized both in photodynamic therapy and to cleave the thioketal linker thereby releasing CPT for chemotherapy.The mitochondria-targeting nanoparticles could elevate photodynamic therapeutic efficacy and induce cell apoptosis.Thus,the blended nanomicelles provide a new promising approach for chemo-and photodynamic combination therapy for lung cancer.3.Here,a mitochondria-targeting thermosensitive liposomes platform was designed and prepared,which can be used in fluorescence imaging,chemo-,photothermal and photodynamic combination therapy.DSPE-PEG2000-NH₂ was coupled with triphenylphosphine to form DSPE-PEG_2K-TPP.The liposomes were self-assembled from DPPC,DSPC,DSPE-PEG_2K-TPP,cholesterol,IR-780 and Lonidamine.Once triphenylphosphine guided the liposomes located inside mitochondria,808 nm laser irradiation could trigger photosensitizer IR-780 to elevate local temperature,which could utilize in photothermal therapy and induce the release of Lonidamine from the thermosensitive liposomes for chemotherapy.Meanwhile,IR-780 could release ROS for photodynamic therapy in mitochondria and increase photodynamic therapeutic efficiency.The liposomes exhibit good biocompatibility and all constituents of the empty liposomes are safe used in human.Few reports were related to IR-780 using in photodynamic therapy and we proved this function of IR-780 again.