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