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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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.

Author information

Author notes

    • Mohammad Ariful Islam

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

    • Michael Lim
    • , Wuji Cao
    •  & James Trevor Oswald

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

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

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.

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.

Corresponding authors

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

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https://doi.org/10.1038/s41551-018-0284-0