Abstract
Tumours growing in a sheet-like manner on the surface of organs and tissues with complex topologies represent a difficult-to-treat clinical scenario. Their complete surgical resection is difficult due to the complicated anatomy of the diseased tissue. Residual cancer often responds poorly to systemic therapy and locoregional treatment is hindered by the limited accessibility to microscopic tumour foci. Here we engineered a peptide-based surface-fill hydrogel (SFH) that can be syringe- or spray-delivered to surface cancers during surgery or used as a primary therapy. Once applied, SFH can shape change in response to alterations in tissue morphology that may occur during surgery. Implanted SFH releases nanoparticles composed of microRNA and intrinsically disordered peptides that enter cancer cells attenuating their oncogenic signature. With a single application, SFH shows efficacy in four preclinical models of mesothelioma, demonstrating the therapeutic impact of the local application of tumour-specific microRNA, which might change the treatment paradigm for mesothelioma and possibly other surface cancers.
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Data availability
The data that support the plots within this paper and other findings of this study are available from the corresponding author upon reasonable request.
References
Hassan, R. et al. Major cancer regressions in mesothelioma after treatment with an anti-mesothelin immunotoxin and immune suppression. Sci. Transl. Med. 5, 208ra147 (2013).
Fisher, J. H. & Child, C. G. 3rd Myasthenia gravis developing acutely after partial removal of a thymoma. N. Engl. J. Med. 252, 891–893 (1955).
Motohara, T. et al. An evolving story of the metastatic voyage of ovarian cancer cells: cellular and molecular orchestration of the adipose-rich metastatic microenvironment. Oncogene 38, 2885–2898 (2019).
Zajac, O. et al. Tumour spheres with inverted polarity drive the formation of peritoneal metastases in patients with hypermethylated colorectal carcinomas. Nat. Cell Biol. 20, 296–306 (2018).
Bueno, R., Opitz, I. & Taskforce, I. M. Surgery in malignant pleural mesothelioma. J. Thorac. Oncol. 13, 1638–1654 (2018).
Wolfe, G. I. et al. Randomized trial of thymectomy in myasthenia gravis. N. Engl. J. Med. 375, 511–522 (2016).
Winner, K. R. K. et al. Spatial modeling of drug delivery routes for treatment of disseminated ovarian cancer. Cancer Res. 76, 1320–1334 (2016).
Jacquet, P. et al. in Peritoneal Carcinomatosis: Principles of Management. Vol. 82 (ed. Sugarbaker, P. H.) 53–63 (Springer, 1996).
Rosenblum, D., Joshi, N., Tao, W., Karp, J. M. & Peer, D. Progress and challenges towards targeted delivery of cancer therapeutics. Nat. Commun. 9, 1410 (2018).
Lu, J. et al. MicroRNA expression profiles classify human cancers. Nature 435, 834–838 (2005).
Rupaimoole, R. & Slack, F. J. MicroRNA therapeutics: towards a new era for the management of cancer and other diseases. Nat. Rev. Drug Discov. 16, 203–222 (2017).
Ling, H., Fabbri, M. & Calin, G. A. MicroRNAs and other non-coding RNAs as targets for anticancer drug development. Nat. Rev. Drug Discov. 12, 847–865 (2013).
Zalcman, G. et al. Bevacizumab for newly diagnosed pleural mesothelioma in the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS): a randomised, controlled, open-label, phase 3 trial. Lancet 387, 1405–1414 (2016).
Baldini, E. H. et al. Updated patterns of failure after multimodality therapy for malignant pleural mesothelioma. J. Thorac. Cardiovasc. Surg. 149, 1374–1381 (2015).
Bertoglio, P., Aprile, V., Ambrogi, M. C., Mussi, A. & Lucchi, M. The role of intracavitary therapies in the treatment of malignant pleural mesothelioma. J. Thorac. Dis. 10, S293–S297 (2018).
Lucchi, M. et al. A phase II study of intrapleural immuno-chemotherapy, pleurectomy/decortication, radiotherapy, systemic chemotherapy and long-term sub-cutaneous IL-2 in stage II-III malignant pleural mesothelioma. Eur. J. Cardiothorac. Surg. 31, 529–533 (2007).
Liu, R. et al. Nanoparticle tumor localization, disruption of autophagosomal trafficking, and prolonged drug delivery improve survival in peritoneal mesothelioma. Biomaterials 102, 175–186 (2016).
Taioli, E. et al. Second primary lung cancers demonstrate better survival with surgery than radiation. Semin. Thorac. Cardiovasc. Surg. 28, 195–200 (2016).
Singh, A. et al. MicroRNA-215-5p treatment suppresses mesothelioma progression via the MDM2-p53-signaling axis. Mol. Ther. 27, 1665–1680 (2019).
Singh, A. et al. microRNA-206 suppresses mesothelioma progression via the Ras signaling axis. Mol. Ther. Nucleic Acids 24, 669–681 (2021).
van Zandwijk, N. et al. Safety and activity of microRNA-loaded minicells in patients with recurrent malignant pleural mesothelioma: a first-in-man, phase 1, open-label, dose-escalation study. Lancet Oncol. 18, 1386–1396 (2017).
Bueno, R. et al. Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations. Nat. Genet. 48, 407–416 (2016).
Xu, Y. et al. miR-1 induces growth arrest and apoptosis in malignant mesothelioma. Chest 144, 1632–1643 (2013).
Cui, X. et al. Enhanced chemotherapeutic efficacy of paclitaxel nanoparticles co-delivered with MicroRNA-7 by inhibiting paclitaxel-induced EGFR/ERK pathway activation for ovarian cancer therapy. ACS Appl. Mater. Interfaces 10, 7821–7831 (2018).
Kasinski, A. L. et al. A combinatorial microRNA therapeutics approach to suppressing non-small cell lung cancer. Oncogene 34, 3547–3555 (2015).
Chen, Y., Gao, D. Y. & Huang, L. In vivo delivery of miRNAs for cancer therapy: challenges and strategies. Adv. Drug Deliv. Rev. 81, 128–141 (2015).
Wang, L. L. et al. Local and sustained miRNA delivery from an injectable hydrogel promotes cardiomyocyte proliferation and functional regeneration after ischemic injury. Nat. Biomed. Eng. 1, 983–992 (2017).
Zhang, X., Li, Y., Chen, Y. E., Chen, J. & Ma, P. X. Cell-free 3D scaffold with two-stage delivery of miRNA-26a to regenerate critical-sized bone defects. Nat. Commun. 7, 10376 (2016).
Saleh, B. et al. Local immunomodulation using an adhesive hydrogel loaded with miRNA-laden nanoparticles promotes wound healing. Small 15, e1902232 (2019).
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. Nat. Mater. 15, 353–363 (2016).
Gilam, A. et al. Local microRNA delivery targets Palladin and prevents metastatic breast cancer. Nat. Commun. 7, 12868 (2016).
Nagy-Smith, K., Moore, E., Schneider, J. & Tycko, R. Molecular structure of monomorphic peptide fibrils within a kinetically trapped hydrogel network. Proc. Natl Acad. Sci. USA 112, 9816–9821 (2015).
Conniot, J. et al. Immunization with mannosylated nanovaccines and inhibition of the immune-suppressing microenvironment sensitizes melanoma to immune checkpoint modulators. Nat. Nanotechnol. 14, 891–901 (2019).
Chen, G. et al. A biodegradable nanocapsule delivers a Cas9 ribonucleoprotein complex for in vivo genome editing. Nat. Nanotechnol. 14, 974–980 (2019).
Cheng, Z., Al Zaki, A., Hui, J. Z., Muzykantov, V. R. & Tsourkas, A. Multifunctional nanoparticles: cost versus benefit of adding targeting and imaging capabilities. Science 338, 903–910 (2012).
Ren, K. et al. A DNA dual lock-and-key strategy for cell-subtype-specific siRNA delivery. Nat. Commun. 7, 13580 (2016).
Chen, W., Deng, W. & Goldys, E. M. Light-triggerable liposomes for enhanced endolysosomal escape and gene silencing in PC12 cells. Mol. Ther. Nucleic Acids 7, 366–377 (2017).
Chen, J. et al. Metal-phenolic coatings as a platform to trigger endosomal escape of nanoparticles. ACS Nano 13, 11653–11664 (2019).
Gillespie, E. J. et al. Selective inhibitor of endosomal trafficking pathways exploited by multiple toxins and viruses. Proc. Natl Acad. Sci. USA 110, E4904–E4912 (2013).
Pruett, N., Singh, A., Shankar, A., Schrump, D. S. & Hoang, C. D. Normal mesothelial cell lines newly derived from human pleural biopsy explants. Am. J. Physiol. Lung Cell. Mol. Physiol. 319, L652–L660 (2020).
Nagy-Smith, K. et al. Molecular, local, and network-level basis for the enhanced stiffness of hydrogel networks formed from coassembled racemic peptides: predictions from Pauling and Corey. ACS Cent. Sci. 3, 586–597 (2017).
Sun, B. et al. Intraperitoneal chemotherapy of ovarian cancer by hydrogel depot of paclitaxel nanocrystals. J. Control. Release 235, 91–98 (2016).
Shankar, G. M. et al. Genotype-targeted local therapy of glioma. Proc. Natl Acad. Sci. USA 115, E8388–E8394 (2018).
National Research Council Guide for Care and Use of Laboratory Animals (National Academies Press, 2011).
Acknowledgements
Funding for this study was provided through the intramural programme of the National Cancer Institute, specifically ZIABC011313 (J.P.S.) and ZIABC011657 (C.D.H.). We acknowledge G. Pauly from the Chemical Biology Laboratory, NCI Frederick (NCI-CBL) for help with videography. We thank T. Lizeth López-Silva for help in figure preparation and P. Beard from the NCI-CBL for administrative help. S. Difilippantonio from the Laboratory Animal Sciences Programme at the NCI Frederick is acknowledged for help with animal experiments.
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Authors and Affiliations
Contributions
C.D.H. and J.P.S. conceived the idea of applying hydrogel for delivering microRNA in mesothelioma. J.P.S. and C.D.H. guided the experiments and provided insight into the final interpretation of the results. P.M. conceived the design of SFH, synthesized materials, performed biophysical and cell-based studies and interpreted the results. A.S. performed cell-based studies, in vivo studies and interpreted the results. Z.W., K.D., C.L., N.d.V. and S.T.R.W. helped in biophysical studies. R.P. helped in tumour resection surgeries. J.S. provided cyclic peptide 1. C.A., A.B.J. and B.K. performed histology. N.L.P. performed imaging. P.M. and A.S. analysed all data. P.M., A.S., C.D.H. and J.P.S. co-wrote the manuscript. All authors discussed the results.
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J.P.S., P.M., C.D.H. and A.S. have filed a patent covering this work. All the other authors have no competing interests.
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Peer review information Nature Nanotechnology thanks Tatiana Segura, Noam Shomron and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
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Extended data
Extended Data Fig. 1 Gating strategies used for the analysis of flow cytometry data.
Panel a, gating strategy used for the experiments shown in Fig. 2l and Supplementary Fig. 10a,c; b, gating strategy used for the experiments shown in Supplementary Fig. 11a; c, gating strategy used for the experiments shown in Fig. 2k and Supplementary Fig. 9a; d, gating strategy used for the experiments shown in Supplementary Fig. 9b. In each case, cell only samples were gated first using FSC and SSC parameters to exclude cell debris and large aggregates. The same gating strategy was applied across all samples in the set. This live population was then used for analysis.
Supplementary information
Supplementary Information
Supplementary Methods, Figs. 1–26 and Tables 1 and 2.
Supplementary Video 1
Spray application of SFH.
Supplementary Video 2
Syringe application of SFH.
Supplementary Video 3
Spread-fill behaviour of SFH during lung re-inflation-A.
Supplementary Video 4
Spread-fill behaviour of SFH during lung re-inflation-B.
Supplementary Video 5
Spread-fill behaviour of SFH during lung re-inflation-C.
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Majumder, P., Singh, A., Wang, Z. et al. Surface-fill hydrogel attenuates the oncogenic signature of complex anatomical surface cancer in a single application. Nat. Nanotechnol. 16, 1251–1259 (2021). https://doi.org/10.1038/s41565-021-00961-w
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DOI: https://doi.org/10.1038/s41565-021-00961-w
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