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, Jinsuck Suh, yongmin Huh, Seungjoo Haam

Research output: Contribution to journalArticle

24 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)12-24
Number of pages13
JournalBiomaterials
Volume105
DOIs
Publication statusPublished - 2016 Oct 1

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Neoplastic Stem Cells
Cell- and Tissue-Based Therapy
Stem cells
MicroRNAs
Stomach Neoplasms
Tumors
Neoplasms
Bearings (structural)
Cells
Cell death
Surface charge
Grafts
Lipids
Lysine
Toxicity
Genes
Therapeutics
Tissue
Nude Mice
Carcinogenesis

All Science Journal Classification (ASJC) codes

  • Bioengineering
  • Ceramics and Composites
  • Biophysics
  • Biomaterials
  • Mechanics of Materials

Cite this

Jang, Eunji ; Kim, Eunjung ; Son, Hye Young ; Lim, Eun Kyung ; Lee, Hwunjae ; Choi, Yuna ; Park, Kwangyeol ; Han, Seungmin ; Suh, Jinsuck ; Huh, yongmin ; Haam, Seungjoo. / Nanovesicle-mediated systemic delivery of microRNA-34a for CD44 overexpressing gastric cancer stem cell therapy. In: Biomaterials. 2016 ; Vol. 105. pp. 12-24.
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Nanovesicle-mediated systemic delivery of microRNA-34a for CD44 overexpressing gastric cancer stem cell therapy. / Jang, Eunji; Kim, Eunjung; Son, Hye Young; Lim, Eun Kyung; Lee, Hwunjae; Choi, Yuna; Park, Kwangyeol; Han, Seungmin; Suh, Jinsuck; Huh, yongmin; Haam, Seungjoo.

In: Biomaterials, Vol. 105, 01.10.2016, p. 12-24.

Research output: Contribution to journalArticle

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AU - Lim, Eun Kyung

AU - Lee, Hwunjae

AU - Choi, Yuna

AU - Park, Kwangyeol

AU - Han, Seungmin

AU - Suh, Jinsuck

AU - Huh, yongmin

AU - Haam, Seungjoo

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