Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Cationic microRNA-delivering nanocarriers for efficient treatment of colon carcinoma in xenograft model

Gene Therapy volume 23, pages 829–838 (2016)Cite this article

Subjects

Abstract

Manipulation of tumor microRNAs (miRNAs) may offer novel avenues for treatment of cancer. However, development of safe, robust, non-viral delivery methods remains a main challenge to obtain the promise of gene therapy. The miR-145 is dysregulated in many cancers, including colon carcer, and further in vitro investigation established antiproliferative and proapoptotic roles of miR-145. Herein, we study a PLGA/PEI (poly (d, l-lactide-co-glycolide)/polyethylenimine)-mediated miRNA vector delivery system; the validation of the method was carried out using a colon cancer xenograft model with miR-145 vector encoding for the expression of miR-145 (pDNA). First, high-molecular-weight PEI (25000 Da) was conjugated with cetyl to formulate reducible cetylated PEI (PEI-cet), and then PEI-cet was introduced to PLGA suspension. Next, PLGA/PEI-cet was crosslinked with hyaluronic acid (HA) to facilitate cellular uptake of miRNA plasmid vector via HA receptor-mediated endocytosis. After local administration of PLGA/PEI/HA complexes, intact miRNA plasmid vectors were delivered into HCT-116 colon cancer cells and xenograft tumor-bearing mice, and significant antitumor effects were achieved. The results show that the HA-based miR-145 nanocarrier could efficiently facilitate cellular uptake and significantly enhance miR-145 expression in HCT-116 cells. Consequently, the increased miR-145 induced G1 cell cycle arrest, reduced tumor proliferation and increased apoptosis, inhibited HCT-116 cell migration and suppressed c-MYC expressions, a regulatory target of miR-145. Of particular importance is the significant decrease in tumor growth in the mice model of colon cancer with the targeting miR-145 delivery system. The results in this work show that miR-145 has been effectively delivered to colon carcinomas through a PLGA/PEI/HA vehicle, indicating a promising miRNA replacement therapy strategy.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  1. Farh KKH, Grimson A, Jan C, Lewis BP, Johnston WK, Lim LP et al. The widespread impact of mammalian microRNAs on mRNA repression and evolution. Science 2005; 310: 1817–1821.

    Article  CAS  Google Scholar 

  2. Mulrane L, McGee SF, Gallagher WM, O'Connor DP . miRNA dysregulation in breast cancer. Cancer Res 2013; 73: 6554–6562.

    Article  CAS  Google Scholar 

  3. Lee H, Choi HJ, Kang CS, Lee HJ, Lee WS, Park CS . Expression of miRNAs and PTEN in endometrial specimens ranging from histologically normal to hyperplasia and endometrial adenocarcinoma. Mod Pathol 2012; 25: 1508–1515.

    Article  CAS  Google Scholar 

  4. Liang G, Li J, Sun B, Li S, Lu L, Wang Y et al. Deep sequencing reveals complex mechanisms of microRNA deregulation in colorectal cancer. Int J Oncol 2014; 45: 603–610.

    Article  CAS  Google Scholar 

  5. Kaur S, Lotsari JE, Al-Sohaily S, Warusavitarne J, Kohonen-Corish MRJ, Peltomaki P . Identification of subgroup-specific miRNA patterns by epigenetic profiling of sporadic and Lynch syndrome-associated colorectal and endometrial carcinoma. Clin Epigenet 2015; 7: 20.

    Article  Google Scholar 

  6. Kasinski AL, Kelnar K, Stahlhut C, Orellana E, Zhao J, Shimer E et al. A combinatorial microRNA therapeutics approach to suppressing non-small cell lung cancer. Oncogene 2015; 34: 3547–3555.

    Article  CAS  Google Scholar 

  7. Ibrahim AF, Weirauch U, Thomas M, Gruenweller A, Hartmann RK, Aigner A . MicroRNA replacement therapy for miR-145 and miR-33a is efficacious in a model of colon carcinoma. Cancer Res 2011; 71: 5214–5224.

    Article  CAS  Google Scholar 

  8. Pagliuca A, Valvo C, Fabrizi E, di Martino S, Biffoni M, Runci D et al. Analysis of the combined action of miR-143 and miR-145 on oncogenic pathways in colorectal cancer cells reveals a coordinate program of gene repression. Oncogene 2013; 32: 4806–4813.

    Article  CAS  Google Scholar 

  9. Yu C-C, Tsai L-L, Wang M-L, Yu C-H, Lo W-L, Chang Y-C et al. miR145 targets the SOX9/ADAM17 axis to inhibit tumor-initiating cells and IL-6-mediated paracrine effects in head and neck cancer. Cancer Res 2013; 73: 3425–3440.

    Article  CAS  Google Scholar 

  10. Lou W, Chen Q, Ma L, Liu J, Yang Z, Shen J et al. Oncolytic adenovirus co-expressing miRNA-34a and IL-24 induces superior antitumor activity in experimental tumor model. J Mol Med 2013; 91: 715–725.

    Article  CAS  Google Scholar 

  11. Merentie M, Lottonen-Raikaslehto L, Parviainen V, Huusko J, Pikkarainen S, Mendel M et al. Efficacy and safety of myocardial gene transfer of adenovirus, adeno-associated virus and lentivirus vectors in the mouse heart. Gene Therapy 2016; 23: 296–305.

    Article  CAS  Google Scholar 

  12. Yoshizawa H, Morishita Y, Watanabe M, Ishibashi K, Muto S, Kusano E et al. TGF-beta(1)-siRNA delivery with nanoparticles inhibits peritoneal fibrosis. Gene Therapy 2015; 22: 333–340.

    Article  CAS  Google Scholar 

  13. Tivnan A, Orr WS, Gubala V, Nooney R, Williams DE, McDonagh C et al. Inhibition of neuroblastoma tumor growth by targeted delivery of microRNA-34a using anti-disialoganglioside GD(2) coated nanoparticles. PLoS One 2012; 7: e38129.

    Article  CAS  Google Scholar 

  14. Liang GF, Zhu YL, Sun B, Hu FH, Tian T, Li SC et al. PLGA-based gene delivering nanoparticle enhance suppression effect of miRNA in HePG2 cells. Nanoscale Res Lett 2011; 6: 447.

    Article  Google Scholar 

  15. Oh EJ, Park K, Kim KS, Kim J, Yang JA, Kong JH et al. Target specific and long-acting delivery of protein, peptide, and nucleotide therapeutics using hyaluronic acid derivatives. J Control Rel 2010; 141: 2–12.

    Article  CAS  Google Scholar 

  16. Toole BP . Hyaluronan: from extracellular glue to pericellular cue. Nat Rev Cancer 2004; 4: 528–539.

    Article  CAS  Google Scholar 

  17. Yao J . Amphoteric hyaluronic acid derivative for targeting gene delivery. Biomaterials 2010; 31: 9357–9365.

    Article  CAS  Google Scholar 

  18. Lee J-Y, Chung S-J, Cho H-J, Kim D-D . Iodinated hyaluronic acid oligomer-based nanoassemblies for tumor-targeted drug delivery and cancer imaging. Biomaterials 2016; 85: 218–231.

    Article  CAS  Google Scholar 

  19. Dosio F, Arpicco S, Stella B, Fattal E . Hyaluronic acid for anticancer drug and nucleic acid delivery. Adv Drug Deliv Rev 2016; 97: 204–236.

    Article  CAS  Google Scholar 

  20. Park K, Lee M-Y, Kim KS, Hahn SK . Target specific tumor treatment by VEGF siRNA complexed with reducible polyethyleneimine-hyaluronic acid conjugate. Biomaterials 2010; 31: 5258–5265.

    Article  CAS  Google Scholar 

  21. Eltoukhy AA, Siegwart DJ, Alabi CA, Rajan JS, Langer R, Anderson DG . Effect of molecular weight of amine end-modified poly(beta-amino ester)s on gene delivery efficiency and toxicity. Biomaterials 2012; 33: 3594–3603.

    Article  CAS  Google Scholar 

  22. Duru N, Fan M, Candas D, Menaa C, Liu H-C, Nantajit D et al. HER2-associated radioresistance of breast cancer stem cells isolated from HER2-negative breast cancer cells. Clin Cancer Res 2012; 18: 6634–6647.

    Article  CAS  Google Scholar 

  23. Mingozzi F . High KA. Immune responses to AAV in clinical trials. Curr Gene Ther 2011; 11: 321–330.

    Article  CAS  Google Scholar 

  24. Ferreira V, Twisk J, Kwikkers K, Aronica E, Brisson D, Methot J et al. Immune responses to intramuscular administration of alipogene tiparvovec (AAV1-LPLS447X) in a phase II clinical trial of lipoprotein lipase deficiency gene therapy. Hum Gene Ther 2014; 25: 180–188.

    Article  CAS  Google Scholar 

  25. Badwaik VD, Aicart E, Mondjinou YA, Johnson MA, Bowman VD, Thompson DH . Structure–property relationship for in vitro siRNA delivery performance of cationic 2-hydroxypropyl-beta-cyclodextrin: PEG-PPG-PEG polyrotaxane vectors. Biomaterials 2016; 84: 86–98.

    Article  CAS  Google Scholar 

  26. Li D, Bu Y, Zhang L, Wang X, Yang Y, Zhuang Y et al. Facile construction of pH- and redox-responsive micelles from a biodegradable poly(beta-hydroxyl amine) for drug delivery. Biomacromolecules 2016; 17: 291–300.

    Article  CAS  Google Scholar 

  27. Kanamala M, Wilson WR, Yang M, Palmer BD, Wu Z . Mechanisms and biomaterials in pH-responsive tumour targeted drug delivery: a review. Biomaterials 2016; 85: 152–167.

    Article  CAS  Google Scholar 

  28. Huang J, Zhang H, Yu Y, Chen Y, Wang D, Zhang G et al. Biodegradable self-assembled nanoparticles of poly (d,l-lactide-co-glycolide)/hyaluronic acid block copolymers for target delivery of docetaxel to breast cancer. Biomaterials 2014; 35: 550–566.

    Article  Google Scholar 

  29. Zhu Y, Liang G, Sun B, Tian T, Hu F, Xiao Z . A novel type of self-assembled nanoparticles as targeted gene carriers: an application for plasmid DNA and antimicroRNA oligonucleotide delivery. Int J Nanomed 2016; 11: 399–411.

    Article  CAS  Google Scholar 

  30. Stano A, Nembrini C, Swartz MA, Hubbell JA, Simeoni E . Nanoparticle size influences the magnitude and quality of mucosal immune responses after intranasal immunization. Vaccine 2012; 30: 7541–7546.

    Article  CAS  Google Scholar 

  31. Niu J, Xue A, Chi Y, Xue J, Wang W, Zhao Z et al. Induction of miRNA-181a by genotoxic treatments promotes chemotherapeutic resistance and metastasis in breast cancer. Oncogene 2016; 35: 1302–1313.

    Article  CAS  Google Scholar 

  32. Li W, Chang J, Wang S, Liu X, Peng J, Huang D et al. miRNA-99b-5p suppresses liver metastasis of colorectal cancer by down-regulating mTOR. Oncotarget 2015; 6: 24448–24462.

    PubMed  PubMed Central  Google Scholar 

  33. Gomes SE, Simoes AES, Pereira DM, Castro RE, Rodrigues CMP, Borralho PM . miR-143 or miR-145 overexpression increases cetuximab-mediated antibody-dependent cellular cytotoxicity in human colon cancer cells. Oncotarget 2016; 7: 9369–9388.

    Article  Google Scholar 

  34. Xue G, Ren Z, Chen Y, Zhu J, Du Y, Pan D et al. A feedback regulation between miR-145 and DNA methyltransferase 3b in prostate cancer cell and their responses to irradiation. Cancer Lett 2015; 361: 121–127.

    Article  CAS  Google Scholar 

  35. Dong R, Liu X, Zhang Q, Jiang Z, Li Y, Wei Y et al. miR-145 inhibits tumor growth and metastasis by targeting metadherin in high-grade serous ovarian carcinoma. Oncotarget 2014; 5: 10816–10829.

    Article  Google Scholar 

  36. Wang G, Zhu S, Gu Y, Chen Q, Liu X, Fu H . MicroRNA-145 and MicroRNA-133a inhibited proliferation, migration, and invasion, while promoted apoptosis in hepatocellular carcinoma cells via targeting FSCN1. Dig Dis Sci 2015; 60: 3044–3052.

    Article  CAS  Google Scholar 

  37. Lee M-Y, Park S-J, Park K, Kim KS, Lee H, Hahn SK . Target-specific gene silencing of layer-by-layer assembled gold-cysteamine/siRNA/PEI/HA nanocomplex. ACS Nano 2011; 5: 6138–6147.

    Article  CAS  Google Scholar 

  38. Liang Gao F, Jing A, Xu J, He X, Chen B . Construction of MiR-145 eukaryotic expression vector and its tumor-suppressive activities in human colon cancer cells. Res J Biotechnol 2014; 9: 79–84.

    Google Scholar 

  39. Yamazaki Y, Nango M, Matsuura M, Hasegawa Y, Hasegawa M, Oku N . Polycation liposomes, a novel nonviral gene transfer system, constructed from cetylated polyethylenimine. Gene Therapy 2000; 7: 1148–1155.

    Article  CAS  Google Scholar 

  40. Andersen MO, Lichawska A, Arpanaei A, Jensen SMR, Kaur H, Oupicky D et al. Surface functionalisation of PLGA nanoparticles for gene silencing. Biomaterials 2010; 31: 5671–5677.

    Article  CAS  Google Scholar 

  41. Ravi Kumar MNV, Bakowsky U, Lehr CM . Preparation and characterization of cationic PLGA nanospheres as DNA carriers. Biomaterials 2004; 25: 1771–1777.

    Article  CAS  Google Scholar 

  42. Livak KJ, Schmittgen TD . Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods (San Diego, Calif.) 2001; 25: 402–408.

    Article  CAS  Google Scholar 

  43. Tsai L-R, Chen M-H, Chien C-T, Chen M-K, Lin F-S, Lin KM-C et al. A single-monomer derived linear-like PEI-co-PEG for siRNA delivery and silencing. Biomaterials 2011; 32: 3647–3653.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was financially supported by the National Natural Science Foundation of China (no. 81370673, 31371003, U1404824), Foundation of He’nan Science & Technology Committee (no.142107000023) and Scientific Research Staring Foundation for Doctors of Henan University of Science and Technology (no. 09001635).

Author information

Authors and Affiliations

  1. School of Medical Technology and Engineering, Henan University of Science and Technology, Luoyang, China

    G Liang, A Jing & W Feng

  2. Department of Hematology and Oncology, Zhongda Hospital, Medical School, Southeast University, Nanjing, China

    G Liang & B Chen

  3. State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing, China

    G Liang, Y Zhu, J Wang, F Hu & Z Xiao

Authors
  1. G Liang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Y Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A Jing
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. F Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. W Feng
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Z Xiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. B Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Z Xiao or B Chen.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liang, G., Zhu, Y., Jing, A. et al. Cationic microRNA-delivering nanocarriers for efficient treatment of colon carcinoma in xenograft model. Gene Ther 23, 829–838 (2016). https://doi.org/10.1038/gt.2016.60

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/gt.2016.60

This article is cited by

Search

Advanced search

Quick links