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

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Abstract

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 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 poly(ethylene glycol) shell. The nanoparticles are stable in serum, elicit low toxicity, enable high PTEN mRNA transfection in prostate cancer cells, and lead to significant inhibition of tumour growth 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 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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Most cited references 50

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Knocking down barriers: advances in siRNA delivery

Kathryn Whitehead, Róbert Miklós Langer, Daniel Anderson (2009)

Key Points RNA interference (RNAi) is a fundamental pathway in eukaryotic cells by which sequence-specific small interfering RNA (siRNA) is able to silence genes through the destruction of complementary mRNA. RNAi is an important therapeutic tool that can be used to silence aberrant endogenous genes or to knockdown genes essential to the proliferation of infectious organisms. Delivery remains the central challenge to the therapeutic application of RNAi technology. Before siRNA can take effect in the cytoplasm of a target cell, it must be transported through the body to the target site without undergoing clearance or degradation. Currently, the most effective synthetic, non-viral delivery agents of siRNA are lipids, lipid-like materials and polymers. Various cationic agents including stable nucleic acid–lipid particles, lipidoids, cyclodextrin polymers and polyethyleneimine polymers have been used to achieve the successful systemic delivery of siRNA in mammals without inducing significant toxicity. Direct conjugation of delivery agents to siRNA can facilitate delivery. For example, cholesterol-modified siRNA enables targeting to the liver. RNAi therapeutics have progressed to the clinic, where studies are being conducted to determine siRNA efficacy in treating several diseases, including age-related macular degeneration and respiratory syncytial virus. Moving forward, it will be important to pay close attention to the potential nonspecific immunostimulatory effects of siRNA. Modifications to siRNA can be used to minimize stimulation of the immune system, and an increased emphasis must be placed on performing proper controls to ensure that therapeutic effects are sequence-specific.

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PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer.

J. Li, C. Yen, D Liaw … (1997)

Mapping of homozygous deletions on human chromosome 10q23 has led to the isolation of a candidate tumor suppressor gene, PTEN, that appears to be mutated at considerable frequency in human cancers. In preliminary screens, mutations of PTEN were detected in 31% (13/42) of glioblastoma cell lines and xenografts, 100% (4/4) of prostate cancer cell lines, 6% (4/65) of breast cancer cell lines and xenografts, and 17% (3/18) of primary glioblastomas. The predicted PTEN product has a protein tyrosine phosphatase domain and extensive homology to tensin, a protein that interacts with actin filaments at focal adhesions. These homologies suggest that PTEN may suppress tumor cell growth by antagonizing protein tyrosine kinases and may regulate tumor cell invasion and metastasis through interactions at focal adhesions.

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The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate.

T Maehama, J. Dixon (1998)

Phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3) is a key molecule involved in cell growth signaling. We demonstrated that overexpression of PTEN, a putative tumor suppressor, reduced insulin-induced PtdIns(3,4,5)P3 production in human 293 cells without effecting insulin-induced phosphoinositide 3-kinase activation. Further, transfection of the catalytically inactive mutant of PTEN (C124S) caused PtdIns(3,4,5)P3 accumulation in the absence of insulin stimulation. Purified recombinant PTEN catalyzed dephosphorylation of PtdIns(3,4,5)P3, specifically at position 3 on the inositol ring. PTEN also exhibited 3-phosphatase activity toward inositol 1,3,4,5-tetrakisphosphate. Our results raise the possibility that PTEN acts in vivo as a phosphoinositide 3-phosphatase by regulating PtdIns(3,4,5)P3 levels. As expected, the C124S mutant of PTEN was incapable of catalyzing dephosphorylation of PtdIns(3,4,5)P3 consistent with the mechanism observed in protein-tyrosine phosphatase-catalyzed reactions.

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Author and article information

Journal

Journal ID (nlm-journal-id): 101696896

Journal ID (pubmed-jr-id): 45929

Journal ID (nlm-ta): Nat Biomed Eng

Journal ID (iso-abbrev): Nat Biomed Eng

Title: Nature biomedical engineering

ISSN (Electronic): 2157-846X

Publication date Nihms-submitted: 19 April 2019

Publication date (Electronic): 17 September 2018

Publication date (Print): November 2018

Publication date PMC-release: 26 April 2019

Volume: 2

Issue: 11

Pages: 850-864

Affiliations

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

[2 ]Vascular Biology Program, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.

[3 ]Hematology Division, Brigham & Women’s Hospital, Boston, Massachusetts, USA.

[4 ]Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.

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

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

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

[8 ]King Abdulaziz University, Jeddah, Saudi Arabia.

Author notes

[* ]Correspondence should be addressed to O.C.F. ( ofarokhzad@ 123456bwh.harvard.edu ), B.R.Z. ( bruce.zetter@ 123456childrens.harvard.edu ) or J.S. ( jshi@ 123456bwh.harvard.edu ).

AUTHOR CONTRIBUTIONS

M.A.I., Y.X., J.S., B.R.Z. and O.C.F. conceived the idea, designed the study and directed the project. M.A.I., Y.X. and W.T. performed all the experiments and analyzed data. W.T., J.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., J.S., B.R.Z. and O.C.F.

[†]

M.A.I., Y.X. and W.T. contributed equally to this work.

Present address of M.L., W.C. and J.T.O.: Nanotechnology Engineering Program, University of Waterloo, Waterloo, Canada.

Article

Manuscript ID: NIHMS1502267

DOI: 10.1038/s41551-018-0284-0

PMC ID: 6486184

PubMed ID: 31015614

SO-VID: bc91c760-c304-4a3a-b47a-5e2fd77cfc1b

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