Exosomes derived from tumor adjacent fibroblasts efficiently target pancreatic tumors  

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作  者:Saini Setua Shabia Shabir Poornima Shaji Ana Martinez Bulnes Anupam Dhasmana Swathi Holla Nivesh K.Mittal Nirakar Sahoo Tripti Saini Francesco Giorgianni Mohammad Sikander Andrew E.Massey Bilal B.Hafeez Manish K.Tripathi Vincent P.Diego Meena Jaggi Junming Yue Nadeem Zafar Murali M.Yallapu Stephen W.Behrman Sheema Khan Subhash C.Chauhan 

机构地区:[1]Department of Pharmaceutical Sciences,College of Pharmacy,and College of Medicine,University of Tennessee Health Science Center(UTHSC),Memphis,TN 36163,USA [2]Department of Computer Science,Islamic University of Science and Technology,Awantipora,J&K 192122,India [3]Department of Immunology and Microbiology,School of Medicine,University of Texas Rio Grande Valley,McAllen,TX 78504,USA [4]South Texas Center of Excellence in Cancer Research,School of Medicine,the University of Texas Rio Grande Valley,McAllen,TX 78504,USA [5]Himalayan School of Biosciences and Cancer Research Institute,Himalayan Institute of Medical Sciences,Swami Rama Himalayan University,Dehradun 248016,India [6]Plough Center for Sterile Drug Delivery Solutions,UTHSC,Memphis,TN 38104,USA [7]Department of Biology,College of Sciences,UTRGV,McAllen,TX 78539,USA [8]National Institute of Biomedical Imaging and Bioengineering(NIBIB),National Institutes of Health,Bethesda,MD 20892,USA [9]South Texas Diabetes and Obesity Institute,UTRGV,McAllen,TX 78504,USA [10]Dept.of Laboratory Medicine&Pathology,University of Washington,Seattle,WA 98195,USA [11]Department of Surgery,Baptist Memorial Medical Education,Baptist Memorial Hospital,Memphis,TN 38120,USA [12]Baptist Health Sciences University,Memphis,TN 38104,USA

出  处:《Acta Pharmaceutica Sinica B》2024年第7期3009-3026,共18页药学学报(英文版)

基  金:UTRGV School of medicine start up,CPRIT TREC Award RP230419 and Integrated Cancer Research Core(ICRC)-RP210180;Herb Kosten foundation for pancreatic cancer research;National Institutes of Health grants R01CA206069,SC1GM139727,SC2GM139715,R01CA210192 and R01CA204552.

摘  要:The application of extracellular vesicles,particularly exosomes(EXs),is rapidly expanding in the field of medicine,owing to their remarkable properties as natural carriers of biological cargo.This study investigates utilization of exosomes derived from stromal cells of tumor adjacent normal tissues(NAF-EXs)for personalized medicine,which can be derived at the time of diagnosis by endoscopic ultrasound.Herein,we show that exosomes(EXs)derived from NAFs demonstrate differential bio-physical characteristics,efficient cellular internalization,drug loading efficiency,pancreatic tumor targeting and delivery of payloads.NAF-derived EXs(NAF-EXs)were used for loading ormeloxifene(ORM),a potent anti-cancer and desmoplasia inhibitor as a model drug.We found that ORM maintains normal fibroblast cell phenotype and renders them incompatible to be triggered for a CAF-like phenotype,which may be due to regulation of Ca^(2+) influx in fibroblast cells.NAF-EXs-ORM effectively blocked oncogenic signaling pathways involved in desmoplasia and epithelial mesenchymal transition(EMT)and repressed tumor growth in xenograft mouse model.In conclusion,our data suggests preferential tropism of NAF-EXs for PDAC tumors,thus imply feasibility of developing a novel personalized medicine for PDAC patients using autologous NAF-EXs for improved therapeutic outcome of anti-cancer drugs.Additionally,it provides the opportunity of utilizing this biological scaffold for effective therapeutics in combination with standard therapeutic regimen.

关 键 词:Pancreatic cancer Tumor adjacent normal tissue fibroblasts(NAF) DESMOPLASIA Extracellular vesicles EXOSOMES Tumor targeting Ormeloxifene Personalized medicine 

分 类 号:R735.9[医药卫生—肿瘤]

 

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