Restoration of tumour-growth suppression in vivo via systemic nanoparticle-mediated delivery of PTEN mRNA
Autor: | Gha Young Lee, James Trevor Oswald, Omid C. Farokhzad, Jessalyn M. Ubellacker, Jinjun Shi, Kun Zhou, Robert Langer, Mi Kyung Yu, Philip W. Kantoff, Michael Lim, Meshkat Dinarvand, Mohammad Ariful Islam, Morteza Mahmoudi, Wuji Cao, Wei Tao, Yingjie Xu, Bruce R. Zetter, Harshal Zope, Daniel Aum |
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Rok vydání: | 2018 |
Předmět: |
Male
0301 basic medicine Biomedical Engineering Mice Nude Medicine (miscellaneous) Apoptosis Bioengineering 02 engineering and technology Transfection Article Polyethylene Glycols Mice Phosphatidylinositol 3-Kinases 03 medical and health sciences Prostate cancer Prostate In vivo Cell Line Tumor medicine Animals Humans Tensin PTEN Tissue Distribution RNA Messenger PI3K/AKT/mTOR pathway Phosphoinositide-3 Kinase Inhibitors Mice Inbred BALB C Messenger RNA biology Chemistry PTEN Phosphohydrolase Prostatic Neoplasms 021001 nanoscience & nanotechnology medicine.disease Lipids 3. Good health Computer Science Applications Disease Models Animal 030104 developmental biology medicine.anatomical_structure Cancer research biology.protein Nanoparticles 0210 nano-technology Proto-Oncogene Proteins c-akt Signal Transduction Biotechnology |
Zdroj: | Nature biomedical engineering |
ISSN: | 2157-846X |
DOI: | 10.1038/s41551-018-0284-0 |
Popis: | 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. |
Databáze: | OpenAIRE |
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