title: Systemic delivery of messenger RNA for the treatment of pancreatic cancer using polyplex nanomicelles with a cholesterol moiety.
abstract: Systemic delivery of messenger RNA (mRNA) is technically challenging because mRNA is highly susceptible to enzymatic degradation in the blood circulation. In this study, we used a nanomicelle-based platform, prepared from mRNA and poly(ethylene glycol) (PEG)-polycation block copolymers. A cholesterol (Chol) moiety was attached to the ω-terminus of the block copolymer to increase the stability of the nanomicelle by hydrophobic interaction. After in vitro screening, polyaspartamide with four aminoethylene repeats in its side chain (PAsp(TEP)) was selected as the cationic segment of the block copolymer, because it contributes to enhance nuclease resistance and high protein expression from the mRNA. After intravenous injection, PEG-PAsp(TEP)-Chol nanomicelles showed significantly enhanced blood retention of mRNA in comparison to nanomicelles without Chol. We used the nanomicelles for treating intractable pancreatic cancer in a subcutaneous inoculation mouse model through the delivery of mRNA encoding an anti-angiogenic protein (sFlt-1). PEG-PAsp(TEP)-Chol nanomicelles generated efficient protein expression from the delivered mRNA in tumor tissue, resulting in remarkable inhibition of the tumor growth, whereas nanomicelles without Chol failed to show a detectable therapeutic effect. In conclusion, the stabilized nanomicelle system led to the successful systemic delivery of mRNA in therapeutic application, holding great promise for the treatment of various diseases.
authors.affiliation: Laboratory of Clinical Biotechnology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Uchida
authors.affiliation: Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, Tokyo, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kinoh
authors.affiliation: Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, Tokyo, Japan.
authors.forename: Takehiko
authors.initials: T
authors.lastname: Ishii
authors.affiliation: Laboratory of Clinical Biotechnology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Akitsugu
authors.initials: A
authors.lastname: Matsui
authors.affiliation: Department of Materials Engineering, Graduate School of Engineering, The University of Tokyo, Tokyo, Japan.
authors.forename: Theofilus Agrios
authors.initials: TA
authors.lastname: Tockary
authors.affiliation: Department of Materials Engineering, Graduate School of Engineering, The University of Tokyo, Tokyo, Japan.
authors.forename: Kaori Machitani
authors.initials: KM
authors.lastname: Takeda
authors.affiliation: Laboratory of Clinical Biotechnology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Hirokuni
authors.initials: H
authors.lastname: Uchida
authors.affiliation: Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, Tokyo, Japan.
authors.forename: Kensuke
authors.initials: K
authors.lastname: Osada
authors.affiliation: Laboratory of Clinical Biotechnology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. Electronic address: itaka-ort@umin.net.
authors.forename: Keiji
authors.initials: K
authors.lastname: Itaka
authors.affiliation: Laboratory of Clinical Biotechnology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, Tokyo, Japan; Department of Materials Engineering, Graduate School of Engineering, The University of Tokyo, Tokyo, Japan. Electronic address: kataoka@bmw.t.u-tokyo.ac.jp.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Kataoka
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000737:chemistry*; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D051379:Mice; D008807:Mice, Inbred BALB C; D008823:Micelles; D053769:Nanocapsules / Q000008:administration & dosage / Q000737:chemistry* / Q000648:ultrastructure; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000473:pathology* / Q000628:therapy*; D010316:Particle Size; D012333:RNA, Messenger / Q000008:administration & dosage*; D016896:Treatment Outcome
chemical_list: D008823:Micelles; D053769:Nanocapsules; D012333:RNA, Messenger; D002784:Cholesterol
keywords: Anti-angiogenic therapy; Cholesterol; Enzymatic degradation; Pancreatic cancer; Polyplex nanomicelle; mRNA delivery