Exosomes derived from tumor adjacent fibroblasts efficiently target pancreatic tumors

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外文摘要：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 ul-trasound.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 Ca2+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 med-icine 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 therapeu-tics in combination with standard therapeutic regimen.

外文关键词：

Pancreatic cancerTumor adjacent normal tissue fibroblasts(NAF)DesmoplasiaExtracellular vesiclesExosomesTumor targetingOrmeloxifenePersonalized medicine

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

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作者单位：

Department of Pharmaceutical Sciences,College of Pharmacy,and College of Medicine,University of Tennessee Health Science Center(UTHSC),Memphis,TN 36163,USA

Department of Computer Science,Islamic University of Science and Technology,Awantipora,J&K 192122,India

Department of Immunology and Microbiology,School of Medicine,University of Texas Rio Grande Valley,McAllen,TX 78504,USA

South Texas Center of Excellence in Cancer Research,School of Medicine,the University of Texas Rio Grande Valley,McAllen,TX 78504,USA

Himalayan School of Biosciences and Cancer Research Institute,Himalayan Institute of Medical Sciences,Swami Rama Himalayan University,Dehradun 248016,India

Plough Center for Sterile Drug Delivery Solutions,UTHSC,Memphis,TN 38104,USA

Department of Biology,College of Sciences,UTRGV McAllen,TX 78539,USA

National Institute of Biomedical Imaging and Bioengineering(NIBIB),National Institutes of Health,Bethesda,MD 20892,USA

South Texas Diabetes and Obesity Institute,UTRGV,McAllen,TX 78504,USA

Dept.of Laboratory Medicine & Pathology,University of Washington,Seattle,WA 98195,USA

Department of Surgery,Baptist Memorial Medical Education,Baptist Memorial Hospital,Memphis,TN 38120,USA

Baptist Health Sciences University,Memphis,TN 38104,USA

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基金：

UTRGV School of medicine start up,CPRIT TRECIntegrated Cancer Research Core(ICRC)Herb Kosten foundation for pancreatic cancer researchNational Institutes of Health grantsNational Institutes of Health grantsNational Institutes of Health grantsNational Institutes of Health grantsNational Institutes of Health grants

项目编号：

RP230419RP210180R01CA206069SC1GM139727SC2GM139715R01CA210192R01CA204552

出版年：

2024

DOI：

10.1016/j.apsb.2024.04.003

药学学报(英文版)

CSTPCD

ISSN：

年,卷(期)：2024.14(7)