title: Potent antitumor effect of neurotensin receptor-targeted oncolytic adenovirus co-expressing decorin and Wnt antagonist in an orthotopic pancreatic tumor model.
abstract: Pancreatic cancer is highly aggressive, malignant, and notoriously difficult to cure using conventional cancer therapies. These conventional therapies have significant limitations due to excessive extracellular matrix (ECM) of pancreatic cancer and poor cancer specificity. The excess ECM prevents infiltration of drugs into the inner layer of the solid tumor. Therefore, novel treatment modalities that can specifically target the tumor and degrade the ECM are required for effective therapy. In the present study, we used ECM-degrading and Wnt signal-disrupting oncolytic adenovirus (oAd/DCN/LRP) to achieve a desirable therapeutic outcome against pancreatic cancer. In addition, to overcome the limitations in systemic delivery of oncolytic Ad (oAd) and to specifically target pancreatic cancer, neurotensin peptide (NT)-conjugated polyethylene glycol (PEG) was chemically crosslinked to the surface of Ad, generating a systemically injectable hybrid system, oAd/DCN/LRP-PEG-NT. We tested the targeting and therapeutic efficacy of oAd/DCN/LRP-PEG-NT toward neurotensin receptor 1 (NTR)-overexpressing pancreatic cancer cells, both in vitro and in vivo. The oAd/DCN/LRP-PEG-NT elicited increased NTR-selective cancer cell killing and transduction efficiency when compared with a cognate control lacking NT (oAd/DCN/LRP-PEG). Furthermore, systemic administration of oAd/DCN/LRP-PEG-NT significantly decreased induction of innate and adaptive immune responses against Ad, and blood retention time was markedly prolonged by PEGylation. Moreover, NTR-targeting oAd elicited greater in vivo tumor growth suppression when compared with naked oAd and 9.5 × 10(6)-fold increased tumor-to-liver ratio. This significantly enhanced antitumor effect of oAd/DCN/LRP-PEG-NT was mediated by active viral replication and viral spreading, which was facilitated by ECM degradation and inhibition of Wnt signaling-related factors (Wnt, β-catenin, and/or vimentin) in the tumor tissues. Taken together, these results demonstrate that oAd/DCN/LRP-PEG-NT has strong therapeutic potential for systemic treatment of NTR-overexpressing pancreatic cancer due to its NTR-targeting ability, enhanced therapeutic efficacy, and safety.
authors.affiliation: Department of Bioengineering, College of Engineering, Hanyang University, Seoul, Korea.
authors.forename: Youjin
authors.initials: Y
authors.lastname: Na
authors.affiliation: Center for Controlled Chemical Delivery, Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Joung-Woo
authors.initials: JW
authors.lastname: Choi
authors.affiliation: Department of Bioengineering, College of Engineering, Hanyang University, Seoul, Korea.
authors.forename: Dayananda
authors.initials: D
authors.lastname: Kasala
authors.affiliation: Department of Bioengineering, College of Engineering, Hanyang University, Seoul, Korea.
authors.forename: JinWoo
authors.initials: J
authors.lastname: Hong
authors.affiliation: Department of Bioengineering, College of Engineering, Hanyang University, Seoul, Korea.
authors.forename: Eonju
authors.initials: E
authors.lastname: Oh
authors.affiliation: Graduate Program for Nanomedical Science, Yonsei University, Seoul, Korea.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Bioengineering, College of Engineering, Hanyang University, Seoul, Korea.
authors.forename: Soo-Jung
authors.initials: SJ
authors.lastname: Jung
authors.affiliation: Department of Bioengineering, College of Engineering, Hanyang University, Seoul, Korea; Center for Controlled Chemical Delivery, Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Sung Wan
authors.initials: SW
authors.lastname: Kim
authors.affiliation: Department of Bioengineering, College of Engineering, Hanyang University, Seoul, Korea. Electronic address: chaeok@hanyang.ac.kr.
authors.forename: Chae-Ok
authors.initials: CO
authors.lastname: Yun
mesh_terms: D056704:Adaptive Immunity; D000256:Adenoviridae / Q000235:genetics* / Q000254:growth & development / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival; D058575:Decorin / Q000096:biosynthesis / Q000235:genetics*; D015967:Gene Expression Regulation, Viral; D015316:Genetic Therapy / Q000009:adverse effects / Q000379:methods*; D006801:Humans; D007113:Immunity, Innate; D008297:Male; D008819:Mice, Nude; D009496:Neurotensin / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology; D050130:Oncolytic Virotherapy / Q000009:adverse effects / Q000379:methods*; D050504:Oncolytic Viruses / Q000235:genetics* / Q000254:growth & development / Q000276:immunology / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy* / Q000821:virology; D011092:Polyethylene Glycols / Q000737:chemistry; D018028:Receptors, Neurotensin / Q000378:metabolism*; D013997:Time Factors; D014161:Transduction, Genetic; D047368:Tumor Burden / Q000187:drug effects*; D019562:Viral Load; D014779:Virus Replication; D060449:Wnt Signaling Pathway / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: D058575:Decorin; D018028:Receptors, Neurotensin; C114036:neurotensin type 1 receptor; D009496:Neurotensin; D011092:Polyethylene Glycols
keywords: Neurotensin; Oncolytic adenovirus; Pancreatic cancer; Systemic administration