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
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