Journal Article

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

Xu, Yingjie, Tao, Wei, Oswald, James Trevor, Zhou, Kun, Mahmoudi, Morteza, Farokhzad, Omid C., Kantoff, Philip W., Lim, Michael, Langer, Robert, Zetter, Bruce R., Yu, Mikyung, Ubellacker, Jessalyn M., Zope, Harshal, Cao, Wuji, Dinarvand, Meshkat, Shi, Jinjun, Aum, Daniel, Islam, Mohammad Ariful, Lee, Gha Young

2018

Overview

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. The reintroduction of PTEN mRNA into PTEN-null prostate cancer cells via encapsulation in polymer–lipid nanoparticles delivered systemically leads to significant inhibition of tumour growth in mouse models of prostate cancer.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 1-Phosphatidylinositol 3-kinase / 13 / 13/106 / 13/109 / 13/2 / 13/31 / 13/51 / 14 / 14/19 / 14/5 / 38 / 42 / 45 / 45/29 / 59 / 631/67/1059/602 / 639/925/352 / 64 / 64/60 / 82 / 96 / 96/21 / 96/63 / AKT protein / Animal models / Animals / Apoptosis / Biocompatibility / Biomedical and Life Sciences / Biomedical Engineering/Biotechnology / Biomedicine / Castration / Cell Line, Tumor / Chromosome 10 / Chromosomes / Disease Models, Animal / Encapsulation / Homology / Humans / Kinases / Lipids / Lipids - chemistry / Male / Metastases / Mice / Mice, Inbred BALB C / Mice, Nude / mRNA / Nanoparticles / Nanoparticles - chemistry / Phosphatidylinositol 3-Kinases - metabolism / Phosphoinositide-3 Kinase Inhibitors / Polyethylene glycol / Polyethylene Glycols - chemistry / Polymers / Prostate cancer / Prostatic Neoplasms - genetics / Prostatic Neoplasms - pathology / Proto-Oncogene Proteins c-akt - antagonists & inhibitors / Proto-Oncogene Proteins c-akt - metabolism / PTEN Phosphohydrolase - deficiency / PTEN Phosphohydrolase - genetics / PTEN protein / Restoration / RNA, Messenger - chemistry / RNA, Messenger - metabolism / Signal Transduction / Tensin / Tissue Distribution / Toxicity / Transfection / Transfection - methods / Tumors