title: Nanovesicle-mediated systemic delivery of microRNA-34a for CD44 overexpressing gastric cancer stem cell therapy.
abstract: The cancer stem cell (CSC) hypothesis postulates that cancer cells overexpressing CD44 are marked as CSCs that cause tumorigenesis and recurrence. This hypothesis suggests that CD44 is a potential therapeutic target that can interfere with CSCs qualities. MicroRNA-34a (miR-34a) is a promising candidate for CD44 repression-based cancer therapy as it has been reported to inhibit proliferation, metastasis, and survival of CD44-positive CSCs. Here, we used nanovesicles containing PLI/miR complexes (NVs/miR) to systemically deliver miR-34a and induce miR-34a-triggered CD44 suppression in orthotopically and subcutaneously implanted tumors in nude mice. Poly(l-lysine-graft-imidazole) (PLI) condenses miRs and is functionally modified to deliver miRs to the site of action by buffering effect of imidazole residues under endosomal pH. Indeed, NVs/miR consisting of PEGylated lipids enveloping PLI/miR complexes greatly reduced inevitable toxicity of polycations by compensating their surface charge and markedly improved their in vivo stability and accumulation to tumor tissue compared to PLI/miR polyplexes. Our NVs-mediated miR-34a delivery system specifically increased endogenous target miR levels, thereby attenuating proliferation and migration of gastric cancer cells by repressing the expression of CD44 with decreased levels of Bcl-2, Oct 3/4 and Nanog genes. Our strategy led to a greater therapeutic outcome than PLI-based delivery with highly selective tumor cell death and significantly delayed tumor growth in CD44-positive tumor-bearing mouse models, thus providing a fundamental therapeutic window for CSCs.
authors: Department of Chemical and Biomolecular Engineering, College of Engineering, Yonsei University, Seoul 120-749, Republic of Korea; Severance Biomedical Science Institute (SBSI), Seoul 120-752, Republic of Korea.
authors: Eunji
authors: E
authors: Jang
authors: Department of Chemical and Biomolecular Engineering, College of Engineering, Yonsei University, Seoul 120-749, Republic of Korea; Department of Materials, Department of Bioengineering and Institute for Biomedical Engineering, Imperial College London, London SW7 2AZ, UK.
authors: Eunjung
authors: E
authors: Kim
authors: Severance Biomedical Science Institute (SBSI), Seoul 120-752, Republic of Korea; Department of Radiology, College of Medicine, Yonsei University, Seoul 120-752, Republic of Korea.
authors: Hye-Young
authors: HY
authors: Son
authors: Hazards Monitoring Bionano Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of Korea; Major of Nanobiotechnology and Bioinformatics, University of Science and Technology, Daejeon 34113, Republic of Korea.
authors: Eun-Kyung
authors: EK
authors: Lim
authors: Severance Biomedical Science Institute (SBSI), Seoul 120-752, Republic of Korea; Nanomedical Interdisciplinary Program, National Core Research Center, Yonsei University, Seoul 120-749, Republic of Korea.
authors: Hwunjae
authors: H
authors: Lee
authors: Severance Biomedical Science Institute (SBSI), Seoul 120-752, Republic of Korea; Department of Radiology, College of Medicine, Yonsei University, Seoul 120-752, Republic of Korea.
authors: Yuna
authors: Y
authors: Choi
authors: Severance Biomedical Science Institute (SBSI), Seoul 120-752, Republic of Korea; Department of Radiology, College of Medicine, Yonsei University, Seoul 120-752, Republic of Korea.
authors: Kwangyeol
authors: K
authors: Park
authors: Department of Chemical and Biomolecular Engineering, College of Engineering, Yonsei University, Seoul 120-749, Republic of Korea.
authors: Seungmin
authors: S
authors: Han
authors: Severance Biomedical Science Institute (SBSI), Seoul 120-752, Republic of Korea; Department of Radiology, College of Medicine, Yonsei University, Seoul 120-752, Republic of Korea; YUHS-KRIBB Medical Convergence Research Institute, Seoul 120-752, Republic of Korea; Brain Korea 21 Project for Medical Science, Yonsei University, College of Medicine, Seoul 120-752, Republic of Korea.
authors: Jin-Suck
authors: JS
authors: Suh
authors: Severance Biomedical Science Institute (SBSI), Seoul 120-752, Republic of Korea; Department of Radiology, College of Medicine, Yonsei University, Seoul 120-752, Republic of Korea; YUHS-KRIBB Medical Convergence Research Institute, Seoul 120-752, Republic of Korea; Brain Korea 21 Project for Medical Science, Yonsei University, College of Medicine, Seoul 120-752, Republic of Korea. Electronic address: ymhuh@yuhs.ac.
authors: Yong-Min
authors: YM
authors: Huh
authors: Department of Chemical and Biomolecular Engineering, College of Engineering, Yonsei University, Seoul 120-749, Republic of Korea. Electronic address: haam@yonsei.ac.kr.
authors: Seungjoo
authors: S
authors: Haam
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000008:administration & dosage*; D058990:Molecular Targeted Therapy / Q000379:methods; D053769:Nanocapsules / Q000008:administration & dosage* / Q000737:chemistry; D058726:Nanoconjugates / Q000008:administration & dosage / Q000737:chemistry; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D013274:Stomach Neoplasms / Q000378:metabolism* / Q000628:therapy*; D016896:Treatment Outcome
chemical_list: C497483:CD44 protein, human; D018960:Hyaluronan Receptors; C522425:MIRN34 microRNA, human; D035683:MicroRNAs; D053769:Nanocapsules; D058726:Nanoconjugates
keywords: CD44 suppression; Cancer stem cells; Nanovesicles; miR-34a delivery; pH-responsive