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

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.

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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.

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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.

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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.

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Correspondence to João Conde or Natalie Artzi.

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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

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