A Rationally Optimized Nanoparticle System for the Delivery of RNA Interference Therapeutics into Pancreatic Tumors in Vivo.
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.
Tumour Biology and Targeting Program, Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Australia , Sydney, New South Wales 2052, Australia.|Australian Centre for NanoMedicine, UNSW Australia , Sydney, New South Wales 2052, Australia.
Joann
J
Teo
Tumour Biology and Targeting Program, Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Australia , Sydney, New South Wales 2052, Australia.|Australian Centre for NanoMedicine, UNSW Australia , Sydney, New South Wales 2052, Australia.
Joshua A
JA
McCarroll
Australian Centre for NanoMedicine, UNSW Australia , Sydney, New South Wales 2052, Australia.|Centre for Advanced Macromolecular Design, School of Chemical Engineering, UNSW Australia , Sydney, New South Wales 2052, Australia.
Cyrille
C
Boyer
Pancreatic Cancer Translational Research Group, Lowy Cancer Research Centre, Prince of Wales Clinical School, UNSW Australia , Sydney, New South Wales 2052, Australia.
Janet
J
Youkhana
Tumour Biology and Targeting Program, Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Australia , Sydney, New South Wales 2052, Australia.|Australian Centre for NanoMedicine, UNSW Australia , Sydney, New South Wales 2052, Australia.
Sharon M
SM
Sagnella
Australian Centre for NanoMedicine, UNSW Australia , Sydney, New South Wales 2052, Australia.|Centre for Advanced Macromolecular Design, School of Chemical Engineering, UNSW Australia , Sydney, New South Wales 2052, Australia.
Hien T T
HT
Duong
Pancreatic Cancer Translational Research Group, Lowy Cancer Research Centre, Prince of Wales Clinical School, UNSW Australia , Sydney, New South Wales 2052, Australia.
Jie
J
Liu
Pancreatic Cancer Translational Research Group, Lowy Cancer Research Centre, Prince of Wales Clinical School, UNSW Australia , Sydney, New South Wales 2052, Australia.
George
G
Sharbeen
Pancreatic Cancer Translational Research Group, Lowy Cancer Research Centre, Prince of Wales Clinical School, UNSW Australia , Sydney, New South Wales 2052, Australia.|Prince of Wales Hospital, Prince of Wales Clinical School , Sydney, New South Wales 2052, Australia.
David
D
Goldstein
ARC Centre of Excellence in Convergent Bio-Nano Science and Technology Monash Institute of Pharmaceutical Sciences, Monash University , Clayton, Victoria 3800, Australia.|Department of Chemistry, University of Warwick , Coventry CV4 7AL, United Kingdom.
Thomas P
TP
Davis
Tumour Biology and Targeting Program, Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Australia , Sydney, New South Wales 2052, Australia.|Australian Centre for NanoMedicine, UNSW Australia , Sydney, New South Wales 2052, Australia.|ARC Centre of Excellence in Convergent Bio-Nano Science and Technology UNSW Australia , Sydney, New South Wales 2052, Australia.
Maria
M
Kavallaris
Australian Centre for NanoMedicine, UNSW Australia , Sydney, New South Wales 2052, Australia.|Pancreatic Cancer Translational Research Group, Lowy Cancer Research Centre, Prince of Wales Clinical School, UNSW Australia , Sydney, New South Wales 2052, Australia.
Phoebe A
PA
Phillips
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D016503:Drug Delivery Systems; D006801:Humans; D008689:Methacrylates / Q000737:chemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D009757:Nylons / Q000737:chemistry; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D011108:Polymers / Q000737:chemistry*; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics*; D014404:Tubulin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D008689:Methacrylates; D009757:Nylons; D011108:Polymers; D034741:RNA, Small Interfering; C498585:TUBB3 protein, human; D014404:Tubulin; C407037:poly(2-(dimethylamino)ethyl methacrylate)