2018·155·
The strength of our newly-propod model was found to be apparent in all cas and manifested most obviously in small target volumes,especially at deeper depths.The prent work demonstrated the advantage of the double Gaussian-logistic model over the others further and made its application in TPS for carbon ion radiotherapy more reliable.
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5-58Exosomes as Drug Carriers for Clinical Application∗
Zhang Hong,Di Cuixia and Li Hongyan
Exosomes denote a family of nano-sized membrane extracellular vesicles with a diameter in the range of40∼130 nm that are creted by most cell types of the body[1].Initial studies suggest that this extracellular vesicle is a metabolic waste that cells crete.However,more and more studies have shown that exosomes act as mediators of cell-to-cell signaling and participate in a variety of physiological and pathological activities in organisms[2].Due to such characteristics,analyzing the speci
fic biomarkers[3]carried therein is expected to be a non-invasive method for diagnosis and monitoring of tumors.Additionally,exosomes are not only important for tumor immunity,tumor invasion,metastasis and tumor resistance,but also has important value in the diagnosis and treatment of tumor. Exosomes can exert important effects in various dia models[4].Overall studies give an idea that exosomes play both cancer-promoting and malignant functions in malignant tumors[5].In order to clarify the potential value of exosomes in tumors,further study of exosome complexity and functional heterogeneity is needed.Exosomes have important conversion values in the diagnosis of tumors,such as the value of liquid biopsy and the value of biomarkers. At the same time,exosomes also have important biological functions in tumorigenesis and development.Tumor cell-derived exosomes may be involved in the host’s menchymal transfer reaction and participate in the antitumor activity of protooncogenes and the formation of the internal environment during the anti-tumor process,promoting or limiting the progression of tumors.Nanocarriers have been extensively investigated for the targeted-delivery of drugs/genes to tumor and inflammatory tissues[6].In particular for tumor tissue,nanocarriers take advantage of the enhanced permeability and retention effect to passively accumulate into tumors[7].Despite decades of intensive investigation of nanocarriers for cancer therapies,there has been limited success in clinical trials due to the lack of safety and inefficient active targeting carriers.Exosomes are novel nanoparticle drug ca
rriers that retain critical nanoparticle characteristics,such as the enhanced permeability and retention effect and passive targeting,but posss additional unique characteristics,such as targeting specificity as well as their intrinsic biological effects on the targeted cells due to the exosome cellular origin[8].
Malignant tumors are one of the most difficult dias in the world today,which have a high mortality rate and a low survival rate.Malignant tumors are treated in a variety of ways,including radiotherapy and chemotherapy, targeting,biological and immunotherapy[9].The methods greatly extend the survival time of patients.At prent, chemotherapy and radiotherapy are the most commonly ud methods.Although chemotherapy and radiotherapy may cau differences in efficacy due to the type and cour of malignancy,chemotherapy resistance and radio tolerance after radiotherapy in tumors have been the major obstacles to cancer therapy[10].Tumors are prone to recurrence and metastasis,which in turn affects patient survival[11].Therefore,to study the caus and mechanisms of drug resistance,and to overcome or rever drug resistance and radiotherapy tolerance accordingly have been the focus of current rearch on cancer therapy.
u盘制作pe系统启动盘The lipid components of exosomes include cholesterol,sphingomyelin,phosphatidylrine and saturated fatty acids,most of which are a biofilm component in plasma[12].Exosomal proteins include
intracellular,plasma,cy-toplasmic proteins and nucleoprotein[13].Exosome-enriched proteins include membrane transport related proteins and fusion proteins such as Rab,annexin,transmembrane transporters(CD9,CD63,CD81and CD82),and also rich in heat shock proteins(HSP70,HSP90),integrin,MHC II protein,human epidermal receptor family and other exosome biosynthesis related proteins[14].The protein composition and content of exosomes depend on the cell type from which it is derived.The earliest reported exosomes contained nucleic acids are microRNAs and mRNAs[15]. Subquently,other types of RNA in exosomes were found,including tRNA,lncRNA and virus RNA[16].By carry-ing different types of RNA,it exerts different functions and influences to the transcription process of the recipient cells,and exerts regulatory functions in signal exchange,organ development,and physiological functions among tissue embryonic cells[17].
·156·2018 Anticancer drug carriers
Traditional drugs often have defects of poor solubility in water,easy to be removed quickly by the human body, poor biocompatibility,poor distribution in the body and low permeability to cells[18].Exosomes as a natural liposome as ideal drug carriers are widely ud at prent[19],which have many advantages over conventional nanocarriers for drug and gene delivery.Exosomes,who
sizes are between40∼130nm,are preferable carriers of genetic drugs,anticancer drugs and other drugs,taking the advantage of their low immunogenicity certain target capability.What kind of exosomes are ideal drug carriers?Johnn et al.[3]pointed out that the u of exosomes for drug delivery requires consideration of the origin of exosomes,methods of purification,types of drug loading,drug loading,and how thefinal drug delivery system is ud.What kind of drugs can exosomes carry? Anticancer drug carriers Traditional chemotherapeutic drugs can be loaded into exosomes for treatment.Recently, two anticancer drugs,paclitaxel and doxorubicin,have been successfully loaded into exosomes[20].The successful delivery of paclitaxel by exosomes in vitro laid the foundation for exosomes carrying anticancer drugs for tumor therapy in vivo.Moreover,Yang et al.[21]demonstrated that exosomes delivered anticancer drugs significantly decreadfluorescent intensity of xenotransplanted cancer cells and tumor growth marker,concluded that brain endothelial cell derived exosomes could be potentially ud as a carrier for brain delivery of anticancer drug for the treatment of brain cancer.Additionally,Qi et al.[22]indicated that drug-loaded exosome-bad vehicle delivery enhanced cancer targeting under an external magneticfield and suppresd tumor growth,which overcame major barriers to the utility of exosomes for cancer application.
Exosome in radiotherapy
Tumor cells can produce anti-radiation effects through hypoxia,tumor cell genetic heterogeneity and DNA repair, et al.After irradiation,tumor cells can crete exosomes and affect the surrounding cells to produce radiotherapy tolerance[23].Khan et al.[24]reported that radiotherapy can induce the increa of the exosomes containing apoptosis inhibitory factor cretion from tumor cells,by which can increa the survival rate of tumor cells and result in radiotherapy tolerance.Soon after,Arscott et al.[25]suggested that exosomes derived from irradiated cells enhanced the migration of recipient cells,and their molecular profiling revealed an abundance of molecules related to signaling pathways important for cell migration,their further studies indicated that radiation influences exosome abundance, specifically alters their molecular composition,and on uptake,promotes a migratory phenotype,due to which tumor cells produce radiotherapy tolerance.In addition,Boelens et al.[26]found that stromal and breast cancer cells utilize paracrine and juxtacrine signaling to drive chemotherapy and radiation resistance,in which the paracrine antiviral and juxtacrine NOTCH3pathways converge as STAT1facilitates transcriptional respons to NOTCH3and expands therapy-resistant tumorinitiating cells,and further primary human and/or mou breast cancer analysis support the role of antiviral/NOTCH3pathways in NOTCH signaling and stroma-mediated resistance.Similarly,revealing the mechanism of radiotherapy tolerance,from a certain point of view helps to improve or solve cancer radiotherapy tolerance in cancer.Richards et al.[27]showed that exo
genetic inhibitors have great potential in the treatment in pancreatic ductal adenocarcinoma with radiotherapy.
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2018·157·
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∗Foundation item:Key Program of National Natural Science Foundation of China(U1432248),Ministry of Science and Technology National Key R&D Project(2016YFC0904600),National Natural Science Foundation of China(Y660010GJ0),Western Talent Program of Chine Academy of Sciences(Y560020XB0)
5-59Study on the Molecular Mechanism of Occurrence and Repair of Cognitive Dysfunction Induced by Carbon Ions Irradiation∗
Liu Yang,Yan Jiawei and Zhang Hong周二早安图片
Carbon ion therapy is a promising modality in radiotherapy to treat tumors[1],however,a potential risk of induction of late normal tissue damage should still be investigated and protected.The aim of the prent study was to explore the long-term cognitive deficits provoked by a high-linear energy transfer(high-LET)carbon ions in mice by targeting to hippocampus which plays a crucial role in memory and learning.Our data showed that,one month after4Gy carbon ion exposure,carbon ion irradiation conspicuously resulted in the impaired cognitive performance, neurodegeneration and neuronal cell death,as well as the reduced mitochondrial integrity,the disrupted activities of tricarboxylic acid cycleflux and electron transport chain,and the depresd antioxidant defen system,conquently leading to a decline of ATP production and persistent oxidative damage in the hippocampus region(Fig.1(a)and (b)).Mechanistically,we demonstrated the disruptions of mitochondrial homeostasis and redox balance typically characterized by the disordered mitochondrial dynamics,mitophagy and glutathione redox couple,which is cloly associated with the inhibitions of PINK1and NRF2signaling pathway as the key regulators of molecular respons in the
context of neurotoxicity and neurodegenerative disorders.Most importantly,we found that administration with melatonin as a mitochondria-targeted antioxidant promoted the PINK1accumulation on the mitochondrial membrane,and augmented the NRF2accumulation and translocation(Fig.1(c)and(d)).Moreover,melatonin
Fig.1(color online)The counteraction of cognitive deficits in the mou model of high-LET carbon ion irradiation.
