https://scholars.lib.ntu.edu.tw/handle/123456789/413048
Title: | Dual Delivery of HNF4α and Cisplatin by Mesoporous Silica Nanoparticles Inhibits Cancer Pluripotency and Tumorigenicity in Hepatoma-Derived CD133-Expressing Stem Cells | Authors: | Tsai, P.-H. Wang, M.-L. Chang, J.-H. Yarmishyn, A.A. Nhi Nguyen, P.N. Chen, W. Chien, Y. Huo, T.-I. Mou, C.-Y. Chiou, S.-H. |
Keywords: | CD133; differentiation therapy; gene delivery; hepatocellular carcinoma; HNF4α; Huh7; mesoporous silica nanoparticles | Issue Date: | 2019 | Journal Volume: | 11 | Journal Issue: | 22 | Start page/Pages: | 19808-19818 | Source: | ACS Applied Materials and Interfaces | Abstract: | Hepatocellular carcinoma (HCC) is one of the most prevalent and deadly malignancies characterized by high rate of recurrence. Tumor recurrence is often attributed to the presence of a subpopulation of cells with stem cell properties, referred to as cancer stem cells (CSCs). Traditionally, cancer therapies target the entire bulk of tumor cells; however, they are poorly effective against CSCs, characterized by higher drug resistance. Therefore, approaches targeting CSCs may be required in addition to conventional chemotherapy to prevent tumor recurrence. In this study, we investigated an approach to target HCC by combining the conventional chemotherapeutic drug, cisplatin, to target the bulk of tumor cells, and differentiation therapy by delivering the gene encoding HNF4α, an important regulator of hepatocyte differentiation, to target CSCs. We used the Huh7 cell line as an in vitro model of HCC, which is characterized by a high proportion of CD133-expressing CSCs. By using flow cytometry, we separated CD133+ and CD133- Huh7 cell subpopulations and have shown that the former has highly pronounced in vivo tumorigenic capacity in contrast to the latter, which could not generate tumors in vivo. For the dual delivery of HNF4α-encoding plasmid and cisplatin, we used polyethyleneimine-modified mesoporous silica nanoparticles (PMSNs) as the nanocarriers. Here, we show that the treatment of CD133-expressing Huh7 cells with HNF4α-loaded PMSNs can suppress their proliferation rate, decrease the proportion of CSCs, downregulate stemness-associated genes, and increase the expression of mature hepatocyte-associated genes. At the same time, the treatment of Huh7 with PMSNs loaded with both HNF4α-encoding plasmid and cisplatin could block them in the S-phase of the cell cycle and cause apoptosis. In addition, dually loaded PMSNs were the most efficient formulation in suppressing tumor growth in vivo. To summarize, in this study, we tested the nanoparticle-based delivery system as both chemotherapy and gene-based therapy agents, which has great potential for development of effective treatment of HCC. ? 2019 American Chemical Society. |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-85066821691&doi=10.1021%2facsami.9b04474&partnerID=40&md5=fca7ebf22d9be5f346c04ac79c881de2 https://scholars.lib.ntu.edu.tw/handle/123456789/413048 |
DOI: | 10.1021/acsami.9b04474 | SDG/Keyword: | Cell culture; Cell death; Chemotherapy; Controlled drug delivery; Diseases; DNA; Encoding (symbols); Gene encoding; Gene expression; Gene therapy; Gene transfer; Mesoporous materials; Nanoparticles; Signal encoding; Silica; Silica nanoparticles; Stem cells; Tumors; CD133; Gene Delivery; Hepatocellular carcinoma; Huh7; Mesoporous silica nanoparticles; Targeted drug delivery; CD133 antigen; cisplatin; hepatocyte nuclear factor 4; HNF4A protein, human; nanoparticle; silicon dioxide; animal; cell cycle; chemistry; drug effect; flow cytometry; genetics; human; liver cell carcinoma; metabolism; mouse; reverse transcription polymerase chain reaction; SCID mouse; stem cell; tumor cell line; TUNEL assay; Western blotting; AC133 Antigen; Animals; Blotting, Western; Carcinoma, Hepatocellular; Cell Cycle; Cell Line, Tumor; Cisplatin; Flow Cytometry; Hepatocyte Nuclear Factor 4; Humans; In Situ Nick-End Labeling; Mice; Mice, SCID; Nanoparticles; Reverse Transcriptase Polymerase Chain Reaction; Silicon Dioxide; Stem Cells |
Appears in Collections: | 化學系 |
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