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.
Subject(s)
Nanoparticles/chemistry , PTEN Phosphohydrolase/genetics , RNA, Messenger/metabolism , Animals , Apoptosis , Cell Line, Tumor , Disease Models, Animal , Humans , Lipids/chemistry , Male , Mice , Mice, Inbred BALB C , Mice, Nude , PTEN Phosphohydrolase/deficiency , Phosphatidylinositol 3-Kinases/metabolism , Phosphoinositide-3 Kinase Inhibitors , Polyethylene Glycols/chemistry , Prostatic Neoplasms/genetics , Prostatic Neoplasms/pathology , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Proto-Oncogene Proteins c-akt/metabolism , RNA, Messenger/chemistry , Signal Transduction , Tissue Distribution , Transfection/methodsABSTRACT
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.
