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Nanovesicle-mediated systemic delivery of microRNA-34a for CD44 overexpressing gastric cancer stem cell therapy

 Eunji Jang  ;  Eunjung Kim  ;  Hye-Young Son  ;  Eun-Kyung Lim  ;  Hwunjae Lee  ;  Yuna Choi  ;  Kwangyeol Park  ;  Seungmin Han  ;  Jin-Suck Suh  ;  , Yong-Min Huh  ;  Seungjoo Haam 
 BIOMATERIALS, Vol.105 : 12-24, 2016 
Journal Title
Issue Date
Animals ; Cell Line, Tumor ; Humans ; Hyaluronan Receptors/metabolism* ; Male ; Mice ; Mice, Inbred BALB C ; MicroRNAs/administration & dosage* ; Molecular Targeted Therapy/methods ; Nanocapsules/administration & dosage* ; Nanocapsules/chemistry ; Nanoconjugates/administration & dosage ; Nanoconjugates/chemistry ; Neoplastic Stem Cells/drug effects* ; Neoplastic Stem Cells/metabolism* ; Neoplastic Stem Cells/pathology ; Stomach Neoplasms/metabolism* ; Stomach Neoplasms/therapy* ; Treatment Outcome
CD44 suppression ; Cancer stem cells ; Nanovesicles ; miR-34a delivery ; pH-responsive
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.
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1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Radiology (영상의학교실) > 1. Journal Papers
Yonsei Authors
Suh, Jin Suck(서진석) ORCID logo https://orcid.org/0000-0001-9455-9240
Son, Hye Yeong(손혜영) ORCID logo https://orcid.org/0000-0001-5977-6784
Huh, Yong Min(허용민) ORCID logo https://orcid.org/0000-0002-9831-4475
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