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Biomacromolecules. 2016 Jul 11;17(7):2337-51. doi: 10.1021/acs.biomac.6b00185. Epub 2016 Jun 28.

A Rationally Optimized Nanoparticle System for the Delivery of RNA Interference Therapeutics into Pancreatic Tumors in Vivo.

Author information

1
Tumour Biology and Targeting Program, Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Australia , Sydney, New South Wales 2052, Australia.
2
Australian Centre for NanoMedicine, UNSW Australia , Sydney, New South Wales 2052, Australia.
3
Centre for Advanced Macromolecular Design, School of Chemical Engineering, UNSW Australia , Sydney, New South Wales 2052, Australia.
4
Pancreatic Cancer Translational Research Group, Lowy Cancer Research Centre, Prince of Wales Clinical School, UNSW Australia , Sydney, New South Wales 2052, Australia.
5
Prince of Wales Hospital, Prince of Wales Clinical School , Sydney, New South Wales 2052, Australia.
6
ARC Centre of Excellence in Convergent Bio-Nano Science and Technology Monash Institute of Pharmaceutical Sciences, Monash University , Clayton, Victoria 3800, Australia.
7
Department of Chemistry, University of Warwick , Coventry CV4 7AL, United Kingdom.
8
ARC Centre of Excellence in Convergent Bio-Nano Science and Technology UNSW Australia , Sydney, New South Wales 2052, Australia.

Abstract

Pancreatic cancer is a devastating disease with a dismal prognosis. Short-interfering RNA (siRNA)-based therapeutics hold promise for the treatment of cancer. However, development of efficient and safe delivery vehicles for siRNA remains a challenge. Here, we describe the synthesis and physicochemical characterization of star polymers (star 1, star 2, star 3) using reversible addition-fragmentation chain transfer polymerization (RAFT) for the delivery of siRNA to pancreatic cancer cells. These star polymers were designed to contain different lengths of cationic poly(dimethylaminoethyl methacrylate) (PDMAEMA) side-arms and varied amounts of poly[oligo(ethylene glycol) methyl ether methacrylate] (POEGMA). We showed that star-POEGMA polymers could readily self-assemble with siRNA to form nanoparticles. The star-POEGMA polymers were nontoxic to normal cells and delivered siRNA with high efficiency to pancreatic cancer cells to silence a gene (TUBB3/βIII-tubulin) which is currently undruggable using chemical agents, and is involved in regulating tumor growth and metastases. Notably, systemic administration of star-POEGMA-siRNA resulted in high accumulation of siRNA to orthotopic pancreatic tumors in mice and silenced βIII-tubulin expression by 80% at the gene and protein levels in pancreatic tumors. Together, these novel findings provide strong rationale for the use of star-POEGMA polymers as delivery vehicles for siRNA to pancreatic tumors.

PMID:
27305597
DOI:
10.1021/acs.biomac.6b00185
[Indexed for MEDLINE]

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