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Restoration of tumour-growth suppression in vivo via systemic nanoparticle-mediated delivery of PTEN mRNA

Nature Biomedical Engineering volume 2, pages 850–864 (2018)Cite this article

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An Author Correction to this article was published on 23 November 2018

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Abstract

Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) is a well-characterized tumour-suppressor gene that is lost or mutated in about half of metastatic castration-resistant prostate cancers and in many other human cancers. The restoration of functional PTEN as a treatment for prostate cancer has, however, proven difficult. Here, we show that PTEN messenger RNA (mRNA) can be reintroduced into PTEN-null prostate cancer cells in vitro and in vivo via its encapsulation in polymer–lipid hybrid nanoparticles coated with a polyethylene glycol shell. The nanoparticles are stable in serum, elicit low toxicity and enable high PTEN mRNA transfection in prostate cancer cells. Moreover, significant inhibition of tumour growth is achieved when delivered systemically in multiple mouse models of prostate cancer. We also show that the restoration of PTEN function in PTEN-null prostate cancer cells inhibits the phosphatidylinositol 3-kinase (PI3K)–AKT pathway and enhances apoptosis. Our findings provide proof-of-principle evidence of the restoration of mRNA-based tumour suppression in vivo.

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Fig. 1: Preparation and characterization of mRNA NPs.
Fig. 2: In vitro toxicity and transfection efficiency of mRNA NPs in PC3 cells.
Fig. 3: In vitro mechanism of PTEN-mRNA-PGCP NP treatment in PC3 cells and its therapeutic effect.
Fig. 4: Effect of lipid–PEG on the pharmacokinetics and biodistribution of mRNA NPs.
Fig. 5: In vivo therapeutic validation of PTEN restoration using PTEN-mRNA NPs in a PCa xenograft model.
Fig. 6: In vivo therapeutic validation of PTEN restoration using PTEN-mRNA NPs in a disseminated metastatic PCa model.
Fig. 7: In vivo therapeutic validation of PTEN restoration using PTEN-mRNA NPs in an intratibial orthotopic PCa model.
Fig. 8: In vivo toxicity studies by histopathological and haematological analyses after treatment of mRNA NPs or PBS.

Data availability

The authors declare that all data supporting the findings of this study are available within the paper and its Supplementary.

Change history

  • 23 November 2018

    The authors wish to add the following sentence into the ‘Competing interests’ section of this Article: “P.W.K. has investment interest in Context Therapeutics LLC, DRGT, Placon, Seer Biosciences and Tarveda Therapeutics, is a company board member for Context Therapeutics LLC, is a consultant and scientific advisory board member for BIND Biosciences, Inc., BN Immunotherapeutics, DRGT, GE Healthcare, Janssen, Metamark, New England Research Institutes, Inc., OncoCellMDX, Progenity, Sanofi, Seer Biosciences, Tarveda Therapeutics and Thermo Fisher, and serves on data safety monitoring boards for Genentech/Roche and Merck.” This has now been included.

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Acknowledgements

This work was in part supported by the Prostate Cancer Foundation (PCF) Young Investigator Award (J.S.); the David Koch-PCF Award in Nanotherapeutics (O.C.F., R.L. and P.W.K.); the US National Institutes of Health (NIH) grants CA200900 (J.S. and B.R.Z.), HL127464 (O.C.F.) and R00CA160350 (J.S.); the National Research Foundation of Korea (K1A1A2048701) (O.C.F.); and the DoD Prostate Cancer Research Program Postdoctoral Training Award (W81XWH-14-1-0268) (Y.X.). The authors would also like to thank E. Reesor, S. Guillemette, J. Rice, Y. Li, M. Zaffagni, D. Bielenberg and J. Wang for their assistance. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

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Author notes

  1. Mohammad Ariful Islam

    Present address: Oncology Division, Immunomic Therapeutics, Inc., Rockville, MD, USA

  2. Michael Lim, Wuji Cao & James Trevor Oswald

    Present address: Nanotechnology Engineering Program, University of Waterloo, Waterloo, Ontario, Canada

  3. These authors contributed equally: Mohammad Ariful Islam, Yingjie Xu, Wei Tao.

Authors and Affiliations

  1. Center for Nanomedicine and Department of Anesthesiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Mohammad Ariful Islam, Wei Tao, Michael Lim, Daniel Aum, Gha Young Lee, Harshal Zope, Mikyung Yu, Wuji Cao, James Trevor Oswald, Meshkat Dinarvand, Morteza Mahmoudi, Omid C. Farokhzad & Jinjun Shi

  2. Vascular Biology Program, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA

    Yingjie Xu, Kun Zhou & Bruce R. Zetter

  3. Hematology Division, Brigham and Women’s Hospital, Boston, MA, USA

    Jessalyn M. Ubellacker

  4. Department of Medicine, Harvard Medical School, Boston, MA, USA

    Jessalyn M. Ubellacker

  5. David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA

    Robert Langer

  6. Institute of Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA

    Robert Langer

  7. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Philip W. Kantoff

  8. King Abdulaziz University, Jeddah, Saudi Arabia

    Omid C. Farokhzad

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Contributions

M.A.I., Y.X., O.C.F., B.R.Z. and J.S. conceived the idea, designed the study and directed the project. M.A.I., Y.X. and W.T. performed all the experiments and analysed data. W.T., J.M.U., K.Z. and G.Y.L. assisted with the metastatic and orthotopic PCa experiments in vivo. M.L., D.A., J.T.O. and W.C. helped in nanoparticle preparation and experimental assays. R.L. provided reagents and conceptual advice. W.T., H.Z., M.Y., M.D., M.M., P.W.K. provided technical support and corrections of manuscript. M.A.I., Y.X. and W.T. wrote the manuscript and revised according to the comments of R.L., P.W.K., O.C.F., B.R.Z. and J.S.

Corresponding authors

Correspondence to Omid C. Farokhzad, Bruce R. Zetter or Jinjun Shi.

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Competing interests

O.C.F. and R.L. declare financial interests in Selecta Biosciences, Tarveda Therapeutics, Placon Therapeutics and Seer. R.L. declares financial interests in Moderna Therapeutics. P.W.K. has investment interest in Context Therapeutics LLC, DRGT, Placon, Seer Biosciences and Tarveda Therapeutics, is a company board member for Context Therapeutics LLC, is a consultant and scientific advisory board member for BIND Biosciences, Inc., BN Immunotherapeutics, DRGT, GE Healthcare, Janssen, Metamark, New England Research Institutes, Inc., OncoCellMDX, Progenity, Sanofi, Seer Biosciences, Tarveda Therapeutics and Thermo Fisher, and serves on data safety monitoring boards for Genentech/Roche and Merck.

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Islam, M.A., Xu, Y., Tao, W. et al. Restoration of tumour-growth suppression in vivo via systemic nanoparticle-mediated delivery of PTEN mRNA. Nat Biomed Eng 2, 850–864 (2018). https://doi.org/10.1038/s41551-018-0284-0

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