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

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• 作者：Eunji Jang^a ; ^b ; ¹ ; Eunjung Kim^a ; ^c ; ¹ ; Hye-Young Son^b ; ^d ; Eun-Kyung Lim^e ; ⁱ ; Hwunjae Lee^b ; ^f ; Yuna Choi^b ; ^d ; Kwangyeol Park^b ; ^d ; Seungmin Han^a ; Jin-Suck Suh^b ; ^d ; ^g ; ^h ; Yong-Min Huh^b ; ^d ; ^g ; ^h ; ^{ymhuh@yuhs.ac" class="auth_mail" title="E-mail the corresponding author} ; Seungjoo Haam^a ; ^{haam@yonsei.ac.kr" class="auth_mail" title="E-mail the corresponding author}
• 关键词：miR-34a delivery ; CD44 suppression ; Cancer stem cells ; Nanovesicles ; pH-responsive
• 刊名：Biomaterials
• 出版年：2016
• 出版时间：October 2016
• 年：2016
• 卷：105
• 期：Complete
• 页码：12-24
• 全文大小：3110 K

文摘

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.