PEI-PEG-Coated Mesoporous Silica Nanoparticles Enhance the Antitumor Activity of Tanshinone IIA and Serve as a Gene Transfer Vector
Correction(s) for this article
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Corrigendum to “PEI-PEG-Coated Mesoporous Silica Nanoparticles Enhance the Antitumor Activity of Tanshinone IIA and Serve as a Gene Transfer Vector”
- Volume 2025Issue 1Evidence-Based Complementary and Alternative Medicine
- First Published online: February 26, 2025
Yinxing Zhu
Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, China njucm.edu.cn
Search for more papers by this authorMiao Yue
Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, China njucm.edu.cn
Search for more papers by this authorTing Guo
Institute of Clinical Medicine, Taizhou People’s Hospital Affiliated to Nantong University, Taizhou, Jiangsu 225300, China ntu.edu.cn
Search for more papers by this authorFang Li
Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, China njucm.edu.cn
Search for more papers by this authorZhifeng Li
Institute of Clinical Medicine, Taizhou People’s Hospital Affiliated to Nantong University, Taizhou, Jiangsu 225300, China ntu.edu.cn
Search for more papers by this authorDazhuang Yang
Institute of Clinical Medicine, Taizhou People’s Hospital Affiliated to Nantong University, Taizhou, Jiangsu 225300, China ntu.edu.cn
Search for more papers by this authorCorresponding Author
Mei Lin
Clinical Laboratory, Taizhou People’s Hospital Affiliated to Nanjing University of Chinese Medicine, Taizhou, Jiangsu 225300, China
Search for more papers by this authorYinxing Zhu
Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, China njucm.edu.cn
Search for more papers by this authorMiao Yue
Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, China njucm.edu.cn
Search for more papers by this authorTing Guo
Institute of Clinical Medicine, Taizhou People’s Hospital Affiliated to Nantong University, Taizhou, Jiangsu 225300, China ntu.edu.cn
Search for more papers by this authorFang Li
Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, China njucm.edu.cn
Search for more papers by this authorZhifeng Li
Institute of Clinical Medicine, Taizhou People’s Hospital Affiliated to Nantong University, Taizhou, Jiangsu 225300, China ntu.edu.cn
Search for more papers by this authorDazhuang Yang
Institute of Clinical Medicine, Taizhou People’s Hospital Affiliated to Nantong University, Taizhou, Jiangsu 225300, China ntu.edu.cn
Search for more papers by this authorCorresponding Author
Mei Lin
Clinical Laboratory, Taizhou People’s Hospital Affiliated to Nanjing University of Chinese Medicine, Taizhou, Jiangsu 225300, China
Search for more papers by this authorAbstract
Tanshinone IIA (TanIIA) and gene therapy both hold promising potentials in hepatocellular carcinoma (HCC) treatment. However, low solubility and poor bioavailability of TanIIA limit its clinical application. Similarly, gene therapy with GPC3-shRNA, a type of short hairpin RNAs (shRNAs) capable of silencing the glypican-3 (GPC3) expression, is seriously limited due to its susceptibility to nuclease degradation and high off-target effects. In the present study, polyethyleneimine (PEI)-polyethylene glycol (PEG)-coated mesoporous silica nanoparticles (MSN-PEG) were used as a drug carrier. By encapsulating TanIIA into MSN-PEG, we synthesized MSN-TanIIA-PEG nanoparticles and observed the involved characteristics. This was followed by exploration of antitumor activity on the HepG2 cell lines in vitro. Meanwhile, in order to construct GPC3-shRNA plasmids, a shRNA sequence targeting GPC3 was synthesized and cloned into the pSLenti-U6 vector. Accordingly, the performance of MSN-PEG as a gene transfer carrier for GPC3-shRNA gene therapy of HCC in vitro was evaluated, including transfection efficiency and DNA binding biological characteristics. The results indicated successful encapsulation of TanIIA in MSN-PEG, which had satisfactory efficacy, favorable dispersity, suitable particle size, and sustained release effect. The in vitro anti-HCC effects of nano-TanIIA were greatly improved, which outperformed free-TanIIA in terms of proliferation and invasion inhibition, as well as apoptosis induction of HCC cells. As expected, MSN-PEG possessed excellent gene delivery capacity with good binding, release, and protection from RNase digestion. Using MSN-PEG as a gene carrier, the plasmids were successfully transfected into HepG2 cells, and both the mRNA and protein expressions of GPC3 were significantly downregulated. It was thus concluded that a sustained release TanIIA delivery system for HCC treatment was synthesized and that MSN-PEG could also serve as a gene transfer carrier for gene therapy. More interestingly, MSN-PEG may be a potential delivery platform that combines TanIIA and GPC3-shRNA together to enhance their synergistic effect.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Open Research
Data Availability
The graphics and quantitative data used to support the findings of this study are included within the article.
References
- 1 Sung H., Ferlay J., Siegel R. L., Laversanne M., Soerjomataram I., Jemal A., and Bray F., Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries, CA: A Cancer Journal for Clinicians. (2021) 71, no. 3, 209–249, https://doi.org/10.3322/caac.21660.
- 2 Hu X., Zhang J., Deng L., Hu H., Hu J., and Zheng G., Galactose-modified PH-sensitive niosomes for controlled release and hepatocellular carcinoma target delivery of tanshinone IIA, AAPS PharmSciTech. (2021) 22, no. 3, https://doi.org/10.1208/s12249-021-01973-4.
- 3 Li L., Zhang X., Pi C., Yang H., Zheng X., Zhao L., and Wei Y., Review of curcumin physicochemical targeting delivery system, International Journal of Nanomedicine. (2020) 15, 9799–9821, https://doi.org/10.2147/ijn.s276201.
- 4 Wang X., Morris-Natschke S. L., and Lee K.-H., New developments in the chemistry and biology of the bioactive constituents of Tanshen, Medicinal Research Reviews. (2007) 27, no. 1, 133–148, https://doi.org/10.1002/med.20077, 2-s2.0-33845768814.
- 5 Fang Z. Y., Zhang M., Liu J. N., Zhao X., Zhang Y. Q., and Fang L., Tanshinone IIA: a review of its anticancer effects, Frontiers in Pharmacology. (2020) 11, 611087, https://doi.org/10.3389/fphar.2020.611087.
- 6 Ansari M. A., Khan F. B., Safdari H. A., Almatroudi A., Alzohairy M. A., Safdari M., Amirizadeh M., Rehman S., Equbal M. J., and Hoque M., Prospective therapeutic potential of Tanshinone IIA: an updated overview, Pharmacological Research. (2021) 164, 105364, https://doi.org/10.1016/j.phrs.2020.105364.
- 7 Zhou Z.-Y., Zhao W.-R., Zhang J., Chen X.-L., and Tang J.-Y., Sodium tanshinone IIA sulfonate: a review of pharmacological activity and pharmacokinetics, Biomedicine & Pharmacotherapy. (2019) 118, 109362, https://doi.org/10.1016/j.biopha.2019.109362, 2-s2.0-85071114881.
- 8 Yan H.-m., Sun E., Cui L., Jia X.-b., and Jin X., Improvement in oral bioavailability and dissolution of tanshinone IIA by preparation of solid dispersions with porous silica, Journal of Pharmacy and Pharmacology. (2015) 67, no. 9, 1207–1214, https://doi.org/10.1111/jphp.12423, 2-s2.0-84939588817.
- 9 Li Z., Zhang Y., Zhang K., Wu Z., and Feng N., Biotinylated-lipid bilayer coated mesoporous silica nanoparticles for improving the bioavailability and anti-leukaemia activity of Tanshinone IIA, Artificial Cells, Nanomedicine, and Biotechnology. (2018) 46, no. sup1, 578–587, https://doi.org/10.1080/21691401.2018.1431651, 2-s2.0-85041221048.
- 10 Moodley T. and Singh M., Sterically stabilised polymeric mesoporous silica nanoparticles improve doxorubicin efficiency: tailored cancer therapy, Molecules. (2020) 25, no. 3, https://doi.org/10.3390/molecules25030742.
- 11 Tang Y., Wang X., Li J., Nie Y., Liao G., Yu Y., and Li C., Overcoming the reticuloendothelial system barrier to drug delivery with a “Don′t-Eat-Us” strategy, ACS Nano. (2019) 13, no. 11, 13015–13026, https://doi.org/10.1021/acsnano.9b05679.
- 12 Yang S., Wang Z., Ping Y., Miao Y., Xiao Y., Qu L., Zhang L., Hu Y., and Wang J., PEG/PEI-functionalized single-walled carbon nanotubes as delivery carriers for doxorubicin: synthesis, characterization, and in vitro evaluation, Beilstein Journal of Nanotechnology. (2020) 11, 1728–1741, https://doi.org/10.3762/bjnano.11.155.
- 13 Zhou F., Shang W., Yu X., and Tian J., Glypican-3: a promising biomarker for hepatocellular carcinoma diagnosis and treatment, Medicinal Research Reviews. (2018) 38, no. 2, 741–767, https://doi.org/10.1002/med.21455, 2-s2.0-85021185872.
- 14 Shih T.-C., Wang L., Wang H.-C., and Wan Y.-J. Y., Glypican-3: a molecular marker for the detection and treatment of hepatocellular carcinoma, Liver Research. (2020) 4, no. 4, 168–172, https://doi.org/10.1016/j.livres.2020.11.003.
- 15 Mroweh M., Decaens T., Marche P. N., Macek Jilkova Z., and Clément F., Modulating the crosstalk between the tumor and its microenvironment using RNA interference: a treatment strategy for hepatocellular carcinoma, International Journal of Molecular Sciences. (2020) 21, no. 15, https://doi.org/10.3390/ijms21155250.
- 16 Acharya R., Prospective vaccination of COVID-19 using shRNA-plasmid-LDH nanoconjugate, Medical Hypotheses. (2020) 143, https://doi.org/10.1016/j.mehy.2020.110084.
- 17 Tian G., Pan R., Zhang B., Qu M., Lian B., Jiang H., Gao Z., and Wu J., Liver-targeted combination therapy basing on glycyrrhizic acid-modified DSPE-PEG-PEI nanoparticles for Co-delivery of doxorubicin and bcl-2 siRNA, Frontiers in Pharmacology. (2019) 10, https://doi.org/10.3389/fphar.2019.00004, 2-s2.0-85065470501.
- 18 Gu Y., Guo Y., Wang C., Xu J., Wu J., Kirk T. B., Ma D., and Xue W., A polyamidoamne dendrimer functionalized graphene oxide for DOX and MMP-9 shRNA plasmid co-delivery, Materials Science and Engineering: C. (2017) 70, no. 1, 572–585, https://doi.org/10.1016/j.msec.2016.09.035, 2-s2.0-84988431140.
- 19 Guo X., Yuan Z., Xu Y., Wei M., Fang Z., and Yuan W.-E., A fluorinated low-molecular-weight PEI/HIF-1α shRNA polyplex system for hemangioma therapy, Biomaterials Science. (2020) 8, no. 8, 2129–2142, https://doi.org/10.1039/d0bm00171f.
- 20 Zhao M., Li J., Ji H., Chen D., and Hu H., A versatile endosome acidity-induced sheddable gene delivery system: increased tumor targeting and enhanced transfection efficiency, International Journal of Nanomedicine. (2019) 14, 6519–6538, https://doi.org/10.2147/ijn.s215250, 2-s2.0-85072114725.
- 21 Li Z., Zhang Y., Zhu C., Guo T., Xia Q., Hou X., Liu W., and Feng N., Folic acid modified lipid-bilayer coated mesoporous silica nanoparticles co-loading paclitaxel and tanshinone IIA for the treatment of acute promyelocytic leukemia, International Journal of Pharmaceutics. (2020) 586, 119576, https://doi.org/10.1016/j.ijpharm.2020.119576.
- 22 Liu X. and Chen X., Determination of tanshinone IIA in radix salviae miltiorrhizae by HPLC, Fujian Analysis and Testing. (2015) 24, no. 1, 36–38.
- 23 Amini Y., Amel Jamehdar S., Sadri K., Zare S., Musavi D., and Tafaghodi M., Different methods to determine the encapsulation efficiency of protein in PLGA nanoparticles, Bio-Medical Materials and Engineering. (2017) 28, no. 6, 613–620, https://doi.org/10.3233/bme-171705, 2-s2.0-85035090038.
- 24 Salinas Y., Brüggemann O., Monkowius U., and Teasdale I., Visible light photocleavable ruthenium-based molecular gates to reversibly control release from mesoporous silica nanoparticles, Nanomaterials. (2020) 10, no. 6, https://doi.org/10.3390/nano10061030.
- 25 Guo T., Dou F., Lin M., Huang J., Zhou C., Zhang J., Yu H., Jiang X., Ye J., Shi Y., Xiao Y., Bian X., Feng X., and Xu N., Biological characteristics and carrier functions of pegylated manganese zinc ferrite nanoparticles, Journal of Nanomaterials. (2019) 2019, 1–10, https://doi.org/10.1155/2019/6854710.
- 26 Ruman U., Fakurazi S., Masarudin M. J., and Hussein M. Z., Nanocarrier-based therapeutics and theranostics drug delivery systems for next generation of liver cancer nanodrug modalities, International Journal of Nanomedicine. (2020) 15, 1437–1456, https://doi.org/10.2147/ijn.s236927.
- 27 Yu J., Zhang J., Xing H., Sun Y., Yang Z., Yang T., Cai C., Zhao X., Yang L., and Ding P., Novel guanidinylated bioresponsive poly(amidoamine)s designed for short hairpin RNA delivery, International Journal of Nanomedicine. (2016) 11, 6651–6666, https://doi.org/10.2147/ijn.s115773, 2-s2.0-85006754060.
- 28 Park D.-H., Cho J., Kwon O.-J., Yun C.-O., and Choy J.-H., Biodegradable inorganic nanovector: passive versus active tumor targeting in siRNA transportation, Angewandte Chemie International Edition. (2016) 55, no. 14, 4582–4586, https://doi.org/10.1002/anie.201510844, 2-s2.0-84976237157.
- 29 Zhang H.-Y., Sun C.-y., Adu-Frimpong M., Yu J.-n., and Xu X.-m., Glutathione-sensitive PEGylated curcumin prodrug nanomicelles: preparation, characterization, cellular uptake and bioavailability evaluation, International Journal of Pharmaceutics. (2019) 555, 270–279, https://doi.org/10.1016/j.ijpharm.2018.11.049, 2-s2.0-85057094003.
- 30 Ceci C., Graziani G., Faraoni I., and Cacciotti I., Strategies to improve ellagic acid bioavailability: from natural or semisynthetic derivatives to nanotechnological approaches based on innovative carriers, Nanotechnology. (2020) 31, no. 38, https://doi.org/10.1088/1361-6528/ab912c.
- 31 Iadnut A., Mamoon K., Thammasit P., Pawichai S., Tima S., Preechasuth K., Kaewkod T., Tragoolpua Y., and Tragoolpua K., In vitro antifungal and antivirulence activities of biologically synthesized ethanolic extract of propolis-loaded PLGA nanoparticles against Candida albicans, Evid Based Complement Alternat Med. (2019) 2019, 14, 3715481, https://doi.org/10.1155/2019/3715481.
- 32 Liu Y., Zheng J., Zhang Y., Wang Z., Yang Y., Bai M., and Dai Y., Fucoxanthin activates apoptosis via inhibition of PI3K/Akt/mTOR pathway and suppresses invasion and migration by restriction of p38-MMP-2/9 pathway in human glioblastoma cells, Neurochemical Research. (2016) 41, no. 10, 2728–2751, https://doi.org/10.1007/s11064-016-1989-7, 2-s2.0-84978151004.
- 33 Teng F., Xu Z., Chen J., Zheng G., Zheng G., Lv H., Wang Y., Wang L., and Cheng X., DUSP1 induces apatinib resistance by activating the MAPK pathway in gastric cancer, Oncology Reports. (2018) 40, no. 3, 1203–1222, https://doi.org/10.3892/or.2018.6520, 2-s2.0-85052027059.
- 34 Sun W., Wang Y., Cai M., Lin L., Chen X., Cao Z., Zhu K., and Shuai X., Codelivery of sorafenib and GPC3 siRNA with PEI-modified liposomes for hepatoma therapy, Biomaterials Science. (2017) 5, no. 12, 2468–2479, https://doi.org/10.1039/c7bm00866j, 2-s2.0-85034835908.
- 35 Huang C.-Y., Chiu T.-L., Kuo S.-J., Chien S.-Y., Chen D.-R., and Su C.-C., Tanshinone IIA inhibits the growth of pancreatic cancer BxPC-3 cells by decreasing protein expression of TCTP, MCL-1 and Bcl-xL, Molecular Medicine Reports. (2013) 7, no. 3, 1045–1049, https://doi.org/10.3892/mmr.2013.1290, 2-s2.0-84873110500.
- 36 Ren X., Wang C., Xie B., Hu L., Chai H., Ding L., Tang L., Xia Y., and Dou X., Tanshinone IIA induced cell death via miR30b-p53-PTPN11/SHP2 signaling pathway in human hepatocellular carcinoma cells, European Journal of Pharmacology. (2017) 796, 233–241, https://doi.org/10.1016/j.ejphar.2016.11.046, 2-s2.0-85009471607.
- 37 Chen F., Zhang J., He Y., Fang X., Wang Y., and Chen M., Glycyrrhetinic acid-decorated and reduction-sensitive micelles to enhance the bioavailability and anti-hepatocellular carcinoma efficacy of tanshinone IIA, Biomaterials Science. (2016) 4, no. 1, 167–182, https://doi.org/10.1039/c5bm00224a, 2-s2.0-84950317066.
- 38 Liao X., Gao Y., Liu J., Tao L., Wang D., Xie D., Mo S., Wang D., Xie D., and Mo S., Combination of tanshinone IIA and cisplatin inhibits esophageal cancer by downregulating NF-κB/COX-2/VEGF pathway, Frontiers in Oncology. (2020) 10, https://doi.org/10.3389/fonc.2020.01756.
- 39 Saqafi B. and Rahbarizadeh F., Polyethyleneimine-polyethylene glycol copolymer targeted by anti-HER2 nanobody for specific delivery of transcriptionally targeted tBid containing construct, Artificial Cells, Nanomedicine, and Biotechnology. (2019) 47, no. 1, 501–511, https://doi.org/10.1080/21691401.2018.1549063, 2-s2.0-85062292358.
