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miR-29b and retinoic acid co-delivery: a promising tool to induce a synergistic antitumoral effect in non-small cell lung cancer cells

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Abstract

The high incidence, late diagnosis, and aggressive profile of lung cancer limit the treatment options, causing a reduced survival rate. Consequently, RNAi-based therapy appears as a potential approach to treat non-small cell lung cancer (NSCLC). This approach is based on the delivery of small RNAs, involved in the regulation of key cell pathways, to treat complex diseases among others. Concerning that, the aim of this work was focused on the co-delivery of miR-29b and retinoic acid (RA) into NSCLC cells by multifunctional micellar nanosystems (Pluronic® P123 or Pluronic® P103 linked to polyethyleneimine (PEI)). The developed P103-PEI-RA/miR-29b (10/1) presented better results and most attractive properties, promoting efficient delivery of miR-29b, as well as revealing a significant antitumoral activity promoted by a synergistic effect between miR-29b expression and RA deliver. Furthermore, the developed therapeutic approach was able to significantly decrease cell viability and migration, as well as induce cell cycle arrest and epigenetic regulation in NSCLC cells. Thus, this work outcome enables to discover a hopeful system to deliver therapeutic miRNAs, crafting a novel RNAi-based therapy combined with RA to treat NSCLC.

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Abbreviations

NSCLC:

non-small cell lung cancer

SCLC:

small cell lung cancer

RA:

retinoic acid

sRNA:

small RNA

RNAi:

RNA interference

miRNA:

microRNA

mRNA:

messenger RNA

3’-UTR:

3′-untranslated region

DNMT :

DNA methyltransferases

CpGi:

CpG islands

FBS:

fetal bovine serum

NC:

scrambled sequence

AV:

annexin V

PI:

propidium iodide

PEI:

polyethyleneimine

DLS:

dynamic light scattering

ELS:

electrophoretic light scattering

EE:

encapsulation efficiency

LE:

loading efficiency

References

  1. Magalhães M, Alvarez-Lorenzo C, Concheiro A, Figueiras A, Santos AC, Veiga F. RNAi-based therapeutics for lung cancer: biomarkers, microRNAs, and nanocarriers. Expert Opin Drug Deliv. 2018;15:965–82.

    Article  Google Scholar 

  2. Herbst RS, Heymach J V, Lippman SM. Molecular origins of cancer lung cancer. N Engl J Med. Massachusetts Medical Society; 2008;359:1367–80.

  3. Cooper WA, Lam DCL, O’Toole SA, Minna JD. Molecular biology of lung cancer. J Thorac Dis. 2013;5(Suppl 5):S479–90.

    PubMed  PubMed Central  Google Scholar 

  4. Pendharkar D, Ausekar BV, Gupta S. Molecular biology of lung cancer-a review. Indian J Surg Oncol. 2013;4:120–4.

    Article  Google Scholar 

  5. Hsu PP, Shaw AT. Lung cancer: a wiley genetic opponent. Cell. Elsevier Inc.; 2017;169:777–9.

  6. Keeler A, Elmallah M, Flotte T. Gene therapy 2017: progress and future directions. Clin Transl Sci. 2017;10:242–8.

    Article  CAS  Google Scholar 

  7. Bobbin ML, Rossi JJ. RNA interference (RNAi)-based therapeutics: delivering on the promise? Annu Rev Pharmacol Toxicol. 2016;56:103–22.

    Article  CAS  Google Scholar 

  8. Castro D, Moreira M, Gouveia AM, Pozza DH, De Mello RA, Castro D, et al. MicroRNAs in lung cancer. Oncotarget. 2017;8:81679–85.

    Article  Google Scholar 

  9. Catalanotto C, Cogoni C, Zardo G. MicroRNA in control of gene expression: an overview of nuclear functions. Int J Mol Sci. 2016;17:1712.

    Article  Google Scholar 

  10. Yan B, Guo Q, Fu FJ, Wang Z, Yin Z, Wei YB, et al. The role of miR-29b in cancer: regulation, function, and signaling. Onco Targets Ther. 2015;8:539–48.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Fabbri M, Garzon R, Cimmino A, Liu Z, Zanesi N, Callegari E, et al. MicroRNA-29 family reverts aberrant methylation in lung cancer by targeting DNA methyltransferases 3A and 3B. Proc Natl Acad Sci U S A. 2007;104:15805–10.

    Article  CAS  Google Scholar 

  12. Dimberg A, Bahram F, Karlberg I, Larsson L, Nilsson K. Retinoic acid–induced cell cycle arrest of human myeloid cell lines is associated with sequential down-regulation of c-Myc and cyclin E and posttranscriptional up-regulation of p27(Kip1). Blood. 2002;99:2199–206.

    Article  CAS  Google Scholar 

  13. Noy N. Between death and survival: retinoic acid in regulation of apoptosis. Annu Rev Nutr. 2010;30:201–17.

    Article  CAS  Google Scholar 

  14. Chen M-C, Hsu S-L, Lin H, Yang T-Y. Retinoic acid and cancer treatment. Biomed. 2014;4:22–7.

    Article  Google Scholar 

  15. Nguyen HK, Lemieux P, Vinogradov SV, Gebhart CL, Guérin N, Paradis G, et al. Evaluation of polyether-polyethyleneimine graft copolymers as gene transfer agents. Gene Ther. 2000;7:126–38.

    Article  CAS  Google Scholar 

  16. Xie YT, Du YZ, Yuan H, Hu FQ. Brain-targeting study of stearic acid-grafted chitosan micelle drug-delivery system. Int J Nanomedicine. 2012;7:3235–44.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Il JY, Chung KD, Kim DH, Kim YH, Lee YS, Choi KC. All-trans retinoic acid-incorporated nanoparticles of deoxycholic acid-conjugated dextran for treatment of CT26 colorectal carcinoma cells. Int J Nanomedicine. 2013;8:485–93.

    Google Scholar 

  18. Magalhães M, Almeida M, Tavares-da-Silva E, Roleira FMF, Varela C, Jorge J, et al. miR-145-loaded micelleplexes as a novel therapeutic strategy to inhibit proliferation and migration of osteosarcoma cells. Eur J Pharm Sci. 2018;123:28–42.

    Article  Google Scholar 

  19. Pereira P, Jorge AF, Martins R, Pais AACC, Sousa F, Figueiras A. Characterization of polyplexes involving small RNA. J Colloid Interface Sci. 2012;387:84–94.

    Article  CAS  Google Scholar 

  20. Magalhães M, Farinha D, de Lima MCP, Faneca H. Increased gene delivery efficiency and specificity of a lipid-based nanosystem incorporating a glycolipid. Int J Nanomedicine. 2014;9:4979–89.

    PubMed  PubMed Central  Google Scholar 

  21. Alameh M, Lavertu M, Tran-Khanh N, Chang C-Y, Lesage F, Bail M, et al. siRNA delivery with chitosan: influence of chitosan molecular weight, degree of deacetylation, and amine to phosphate ratio on in vitro silencing efficiency, hemocompatibility, biodistribution, and in vivo efficacy. Biomacromolecules. 2018;19:112–31.

    Article  CAS  Google Scholar 

  22. Zhao ZX, Gao SY, Wang JC, Chen CJ, Zhao EY, Hou WJ, Feng Q, Gao LY, Liu XY, Zhang LR, Zhang Q Self-assembly nanomicelles based on cationic mPEG-PLA-b-Polyarginine(R15) triblock copolymer for siRNA delivery. Biomaterials. Elsevier Ltd; 2012;33:6793–807.

  23. Fritz H, Kennedy D, Fergusson D, Fernandes R, Doucette S, Cooley K, et al. Vitamin A and retinoid derivatives for lung cancer: a systematic review and meta analysis. PLoS One. 2011;6:e21107.

  24. Zhang W, Xu J. DNA methyltransferases and their roles in tumorigenesis. Biomark Res. 2017;5:1–8.

    Article  Google Scholar 

  25. Morita S, Horii T, Kimura M, Ochiya T, Tajima S, Hatada I. miR-29 represses the activities of DNA methyltransferases and DNA demethylases. Int J Mol Sci. 2013;14:14647–58.

  26. Magalhães M, Figueiras A, Veiga F. Smart micelleplexes: an overview of a promising and potential nanocarrier for alternative therapies. In: Grumezescu A, editor. Des Dev new nanocarriers. William Andrew Publishing; 2018;14:257–91.

  27. Simões SM, Figueiras AR, Veiga F, Concheiro A, Alvarez-Lorenzo C. Polymeric micelles for oral drug administration enabling locoregional and systemic treatments. Expert Opin Drug Deliv. 2015;12:297–318.

    Article  Google Scholar 

  28. Forest V, Pourchez J. Preferential binding of positive nanoparticles on cell membranes is due to electrostatic interactions: a too simplistic explanation that does not take into account the nanoparticle protein corona. Mater Sci Eng C. Elsevier B.V.; 2017;70:889–96.

  29. Jiang H, Zhang G, Wu JH, Jiang CP. Diverse roles of miR-29 in cancer (review). Oncol Rep. 2014;31:1509–16.

    Article  CAS  Google Scholar 

  30. Bartek J, Lukas J. Mammalian G1- and S-phase checkpoints in response to DNA damage. Curr Opin Cell Biol. 2001;13:738–47.

    Article  CAS  Google Scholar 

  31. Siu KT, Rosner MR, Minella AC. An integrated view of cyclin E function and regulation. Cell Cycle. 2012;11:57–64.

    Article  CAS  Google Scholar 

  32. Garzon R, Liu S, Fabbri M, Liu Z, Heaphy CEA, Callegari E, et al. MicroRNA-29b induces global DNA hypomethylation and tumor suppressor gene reexpression in acute myeloid leukemia by targeting directly DNMT3A and 3B and indirectly DNMT1. Blood. 2019;113:6411–8.

    Article  Google Scholar 

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Acknowledgments

Authors would like to thank UCQPharma, Faculty of Pharmacy, University of Coimbra by the FTIR spectra acquisition, Laboratory of Bio-Imaging and Electron Microscopy, Faculty of Medicine, University of Coimbra by the TEM images acquired, and to Professor Fani Sousa (Health Sciences Research Centre, University of Beira Interior) for kindly providing the knowledge, facilities and means to the production of the sRNA samples. NMR data were collected at the UC-NMR facility which is supported in part by FEDER through the COMPETE Program (Operational Program for Competitiveness) and by Fundação para a Ciência e Tecnologia through the grants REEQ/481/QUI/2006, RECI/QEQ-QFI/0168/2012, CENTRO-07-CT62-FEDER-002012, and Rede Nacional de Ressonância Magnética Nuclear (RNRMN).

Funding

This work received financial support from Portugal National Funds (FCT/MEC, Fundação para a Ciência e Tecnologia/Ministério da Educação e Ciência) through project UID/QUI/50006/2013, co-financed by European Union (FEDER under the Partnership Agreement PT2020). It was also supported by the Research Project POCI-01-0145-FEDER-016642 and the grant FCT PTDC/CTM-BIO/1518/2014 from Fundação para a Ciência e Tecnologia (FCT) and the European Community Fund (FEDER) through the COMPETE2020 program.

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Authors and Affiliations

  1. Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra, Azinhaga de Santa Comba, 3000-548, Coimbra, Portugal

    Mariana Magalhães, Ana Figueiras, Ana Cláudia Santos & Francisco Veiga

  2. REQUIMTE/LAQV, Group of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra, Azinhaga de Santa Comba, 3000-548, Coimbra, Portugal

    Mariana Magalhães, Rui Carvalho, Ana Figueiras, Ana Cláudia Santos & Francisco Veiga

  3. Laboratory of Oncobiology and Hematology, University Clinic of Hematology and Applied Molecular Biology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal

    Joana Jorge, Ana Cristina Gonçalves & Ana Bela Sarmento-Ribeiro

  4. Coimbra Institute for Clinical and Biomedical Research (iCBR), Group of Environment Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, Coimbra, Portugal

    Joana Jorge, Ana Cristina Gonçalves & Ana Bela Sarmento-Ribeiro

  5. Clinical Hematology Department, Centro Hospitalar e Universitário de Coimbra (CHUC), Coimbra, Portugal

    Ana Bela Sarmento-Ribeiro

  6. Department of Life Sciences, Faculty of Sciences and Technology, University of Coimbra, Coimbra, Portugal

    Rui Carvalho

Authors
  1. Mariana Magalhães
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  2. Joana Jorge
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  3. Ana Cristina Gonçalves
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  4. Ana Bela Sarmento-Ribeiro
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  5. Rui Carvalho
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  6. Ana Figueiras
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  7. Ana Cláudia Santos
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  8. Francisco Veiga
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Correspondence to Mariana Magalhães or Francisco Veiga.

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Magalhães, M., Jorge, J., Gonçalves, A.C. et al. miR-29b and retinoic acid co-delivery: a promising tool to induce a synergistic antitumoral effect in non-small cell lung cancer cells. Drug Deliv. and Transl. Res. 10, 1367–1380 (2020). https://doi.org/10.1007/s13346-020-00768-7

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