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.

Local triple-combination therapy results in tumour regression and prevents recurrence in a colon cancer model

Nature Materials volume 15, pages 1128–1138 (2016)Cite this article

Subjects

Abstract

Conventional cancer therapies involve the systemic delivery of anticancer agents that neither discriminate between cancer and normal cells nor eliminate the risk of cancer recurrence. Here, we demonstrate that the combination of gene, drug and phototherapy delivered through a prophylactic hydrogel patch leads, in a colon cancer mouse model, to complete tumour remission when applied to non-resected tumours and to the absence of tumour recurrence when applied following tumour resection. The adhesive hydrogel patch enhanced the stability and provided local delivery of embedded nanoparticles. Spherical gold nanoparticles were used as a first wave of treatment to deliver siRNAs against Kras, a key oncogene driver, and rod-shaped gold nanoparticles mediated the conversion of near-infrared radiation into heat, causing the release of a chemotherapeutic as well as thermally induced cell damage. This local, triple-combination therapy can be adapted to other cancer cell types and to molecular targets associated with disease progression.

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

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

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

Figure 1: The rationale behind the design of local triple-combination therapy.
Figure 2: Functional characterization and in vitro performance.
Figure 3: Selective and efficient local triple therapy improves CRC therapeutic efficacy.
Figure 4: Local triple-therapy combination results in complete tumour regression and recurrence elimination before and after tumour resection, respectively.
Figure 5: Altered tumour genetic profile in response to local therapy treatment.
Figure 6: Canonical pathway kinetics in triple-therapy combination.

References

  1. Siegel, R. L., Miller, K. D. & Jemal, A. Cancer statistics, 2016. CA Cancer J. Clin. 66, 7–30 (2016).

    Article  Google Scholar 

  2. Kistler, C. E. Colorectal-cancer incidence and mortality after screening. N. Engl. J. Med. 369, 2354–2354 (2013).

    Article  CAS  Google Scholar 

  3. Kountouras, J., Zavos, C. & Chatzopoulos, D. Therapy for colorectal cancer. N. Engl. J. Med. 352, 1820–1821 (2005).

    Article  CAS  Google Scholar 

  4. Minelli, C., Lowe, S. B. & Stevens, M. M. Engineering nanocomposite materials for cancer therapy. Small 6, 2336–2357 (2010).

    Article  CAS  Google Scholar 

  5. Liu, Y., Miyoshi, H. & Nakamura, M. Nanomedicine for drug delivery and imaging: a promising avenue for cancer therapy and diagnosis using targeted functional nanoparticles. Int. J. Cancer 120, 2527–2537 (2007).

    Article  CAS  Google Scholar 

  6. Conde, J., Oliva, N., Atilano, M., Song, H. S. & Artzi, N. Self-assembled RNA-triple-helix hydrogel scaffold for microRNA modulation in the tumour microenvironment. Nature Mater. 15, 353–363 (2016).

    Article  CAS  Google Scholar 

  7. Howes, P. D., Chandrawati, R. & Stevens, M. M. Colloidal nanoparticles as advanced biological sensors. Science 346, 1247390 (2014).

    Article  Google Scholar 

  8. Wu, S. Y., Lopez-Berestein, G., Calin, G. A. & Sood, A. K. RNAi therapies: drugging the undruggable. Sci. Transl. Med. 6, 240ps7 (2014).

    Article  Google Scholar 

  9. Bertrand, N., Wu, J., Xu, X., Kamaly, N. & Farokhzad, O. C. Cancer nanotechnology: the impact of passive and active targeting in the era of modern cancer biology. Adv. Drug Deliv. Rev. 66, 2–25 (2014).

    Article  CAS  Google Scholar 

  10. Conde, J., Edelman, E. R. & Artzi, N. Target-responsive DNA/RNA nanomaterials for microRNA sensing and inhibition: the jack-of-all-trades in cancer nanotheranostics? Adv. Drug Deliv. Rev. 81, 169–183 (2015).

    Article  CAS  Google Scholar 

  11. Oliva, N. et al. Regulation of dendrimer/dextran material performance by altered tissue microenvironment in inflammation and neoplasia. Sci. Transl. Med. 7, 272ra211 (2015).

    Article  Google Scholar 

  12. Segovia, N. et al. Hydrogel doped with nanoparticles for local sustained release of siRNA in breast cancer. Adv. Healthc. Mater. 4, 271–280 (2015).

    Article  CAS  Google Scholar 

  13. Conde, J., Oliva, N. & Artzi, N. Implantable hydrogel embedded dark-gold nanoswitch as a theranostic probe to sense and overcome cancer multidrug resistance. Proc. Natl Acad. Sci. USA 112, E1278–E1287 (2015).

    Article  CAS  Google Scholar 

  14. Artzi, N. et al. In vivo and in vitro tracking of erosion in biodegradable materials using non-invasive fluorescence imaging. Nature Mater. 10, 704–709 (2011).

    CAS  Google Scholar 

  15. Artzi, N., Shazly, T., Baker, A. B., Bon, A. & Edelman, E. R. Aldehyde-amine chemistry enables modulated biosealants with tissue-specific adhesion. Adv. Mater. 21, 3399–3403 (2009).

    Article  CAS  Google Scholar 

  16. von Maltzahn, G. et al. Computationally guided photothermal tumor therapy using long-circulating gold nanorod antennas. Cancer Res. 69, 3892–3900 (2009).

    Article  CAS  Google Scholar 

  17. Huang, X., El-Sayed, I. H., Qian, W. & El-Sayed, M. A. Cancer cell imaging and photothermal therapy in the near-infrared region by using gold nanorods. J. Am. Chem. Soc. 128, 2115–2120 (2006).

    Article  CAS  Google Scholar 

  18. von, M. G. et al. Nanoparticles that communicate in vivo to amplify tumour targeting. Nature Mater. 10, 545–552 (2011).

    Article  Google Scholar 

  19. Sonpavde, G. Bevacizumab in colorectal cancer. N. Engl. J. Med. 351, 1690 (2004).

    Article  CAS  Google Scholar 

  20. Wang, Y., Fei, D., Vanderlaan, M. & Song, A. Biological activity of bevacizumab, a humanized anti-VEGF antibody in vitro. Angiogenesis 7, 335–345 (2004).

    Article  CAS  Google Scholar 

  21. Li, Z. J. et al. A novel peptide specifically targeting the vasculature of orthotopic colorectal cancer for imaging detection and drug delivery. J. Control. Release 148, 292–302 (2010).

    Article  CAS  Google Scholar 

  22. Sunakawa, Y., Lenz, H. J. & Ichikawa, W. RAS mutations in colorectal cancer. N. Engl. J. Med. 369, 2159 (2013).

    Article  CAS  Google Scholar 

  23. Bosch, F. X., Garten, W., Klenk, H. D. & Rott, R. Proteolytic cleavage of influenza-virus hemagglutinins—primary structure of the connecting peptide between Ha1 and Ha2 determines proteolytic cleavability and pathogenicity of avian influenza-viruses. Virology 113, 725–735 (1981).

    Article  CAS  Google Scholar 

  24. Oliva, N. et al. Natural tissue microenvironmental conditions modulate adhesive material performance. Langmuir 28, 15402–15409 (2012).

    Article  CAS  Google Scholar 

  25. Wang, Y. H. et al. Synergistic delivery of gold nanorods using multifunctional microbubbles for enhanced plasmonic photothermal therapy. Sci. Rep. 4, 5685 (2014).

    Article  CAS  Google Scholar 

  26. Kuo, W. S. et al. Gold nanorods in photodynamic therapy, as hyperthermia agents, and in near-infrared optical imaging. Angew. Chem. Int. Ed. Engl. 49, 2711–2715 (2010).

    Article  CAS  Google Scholar 

  27. Chong, P. S. & Finlay, I. G. Surgical options in the management of advanced and recurrent colorectal cancer. Surg. Oncol. 16, 25–31 (2007).

    Article  Google Scholar 

  28. Chokshi, R. J., Abdel-Misih, S. & Bloomston, M. Surgical management of colorectal cancer: a review of the literature. Indian J. Surg. 71, 350–355 (2009).

    Article  Google Scholar 

  29. Mocellin, S. Microarray Technology and Cancer Gene Profiling. Advances in Experimental Medicine and Biology (Springer, 2007).

    Book  Google Scholar 

  30. Adiconis, X. et al. Comparative analysis of RNA sequencing methods for degraded or low-input samples. Nature Methods 10, 623–629 (2013).

    Article  CAS  Google Scholar 

  31. Hemmat, M. et al. Short stature, digit anomalies and dysmorphic facial features are associated with the duplication of miR-17 ∼ 92 cluster. Mol. Cytogenet. 7, 27 (2014).

    Article  Google Scholar 

  32. Lu, J. et al. MicroRNA expression profiles classify human cancers. Nature 435, 834–838 (2005).

    Article  CAS  Google Scholar 

  33. Mendell, J. T. miRiad roles for the miR-17-92 cluster in development and disease. Cell 133, 217–222 (2008).

    Article  CAS  Google Scholar 

  34. Hatakeyama, H. et al. A DNA microarray-based analysis of the host response to a nonviral gene carrier: a strategy for improving the immune response. Mol. Ther. 19, 1487–1498 (2011).

    Article  CAS  Google Scholar 

  35. Meerzaman, D. M. et al. Genome-wide transcriptional sequencing identifies novel mutations in metabolic genes in human hepatocellular carcinoma. Cancer Genomics Proteomics 11, 1–12 (2014).

    Google Scholar 

  36. Voloshanenko, O. et al. Wnt secretion is required to maintain high levels of Wnt activity in colon cancer cells. Nature Commun. 4, 2610 (2013).

    Article  Google Scholar 

  37. Herath, N. I., Doecke, J., Spanevello, M. D., Leggett, B. A. & Boyd, A. W. Epigenetic silencing of EphA1 expression in colorectal cancer is correlated with poor survival. Br. J. Cancer 100, 1095–1102 (2009).

    Article  CAS  Google Scholar 

  38. Kok-Sin, T. et al. Identification of diagnostic markers in colorectal cancer via integrative epigenomics and genomics data. Oncol. Rep. 34, 22–32 (2015).

    Article  CAS  Google Scholar 

  39. Sturn, A., Quackenbush, J. & Trajanoski, Z. Genesis: cluster analysis of microarray data. Bioinformatics 18, 207–208 (2002).

    Article  CAS  Google Scholar 

  40. Mootha, V. K. et al. PGC-1 alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nature Genet. 34, 267–273 (2003).

    Article  CAS  Google Scholar 

  41. Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl Acad. Sci. USA 102, 15545–15550 (2005).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

J.C. acknowledges Marie Curie International Outgoing Fellowship and Funding (FP7-PEOPLE-2013-IOF, Project 626386). We thank the Swanson Biotechnology Center at the Koch Institute for Integrative Cancer Research at Massachusetts Institute of Technology (MIT) for assistance with animal experiments and facilities, especially the microscopy, flow cytometry, and histology cores. We also acknowledge that all qPCR and microarray experiments done in the KI Genomics Core/MIT BioMicro Center are funded by the NIH and supported in part by the Koch Institute Support Grant P30-CA14051 from the National Cancer Institute and by the National Institute of Environmental Health Sciences of the NIH under award P30-ES002109. We thank D. Ma and C. Whittaker from the Bioinformatics and Computing Core Facility at David H. Koch Institute for Integrative Cancer Research at MIT for the microarrays analysis. We thank D. S. Yun for cryo-TEM assistance at the Peterson Nanotechnology Materials Core Facility. We thank the Department of Comparative Medicine at MIT, especially J. Haupt. We thank G. Paradis for FACS assistance with Cancer Center Support (FACS core) Grant P30-CA14051 from the National Cancer Institute. We thank P. Boisvert and Y. Zhang for technical assistance in SEM at the MIT Center for Materials Science and Engineering (CMSE). These SEM studies made use of the MRSEC Shared Experimental Facilities at MIT, supported by the National Science Foundation under award number DMR-1419807.

Author information

Authors and Affiliations

  1. Massachusetts Institute of Technology, Institute for Medical Engineering and Science, Cambridge, Massachusetts 02139, USA

    João Conde, Nuria Oliva, Yi Zhang & Natalie Artzi

  2. School of Engineering and Materials Science, Queen Mary University of London, London E1 4NS, UK

    João Conde

  3. Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA

    Natalie Artzi

  4. Department of Medicine, Division of Biomedical Engineering, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA

    Natalie Artzi

Authors
  1. João Conde
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nuria Oliva
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yi Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Natalie Artzi
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

J.C. and N.A. conceived the project and designed the experiments. J.C. and N.O. performed the experiments, and collected and analysed the data. Y.Z. performed the SEM studies. J.C. and N.A. co-wrote the manuscript. All authors discussed the results and reviewed the manuscript.

Corresponding authors

Correspondence to João Conde or Natalie Artzi.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

Supplementary information (PDF 4166 kb)

Rights and permissions

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Conde, J., Oliva, N., Zhang, Y. et al. Local triple-combination therapy results in tumour regression and prevents recurrence in a colon cancer model. Nature Mater 15, 1128–1138 (2016). https://doi.org/10.1038/nmat4707

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nmat4707

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing