title: Effective delivery of siRNA into cancer cells and tumors using well-defined biodegradable cationic star polymers.
abstract: Cancer is one of the most common causes of death worldwide. Two types of cancer that have high mortality rates are pancreatic and lung cancer. Despite improvements in treatment strategies, resistance to chemotherapy and the presence of metastases are common. Therefore, novel therapies which target and silence genes involved in regulating these processes are required. Short-interfering RNA (siRNA) holds great promise as a therapeutic to silence disease-causing genes. However, siRNA requires a delivery vehicle to enter the cell to allow it to silence its target gene. Herein, we report on the design and synthesis of cationic star polymers as novel delivery vehicles for siRNA to silence genes in pancreatic and lung cancer cells. Dimethylaminoethyl methacrylate (DMAEMA) was polymerized via reversible addition-fragmentation transfer polymerization (RAFT) and then chain extended in the presence of both cross-linkers N,N-bis(acryloyl)cistamine and DMAEMA, yielding biodegradable well-defined star polymers. The star polymers were characterized by transmission electron microscopy, dynamic light scattering, ζ potential, and gel permeation chromatography. Importantly, the star polymers were able to self-assemble with siRNA and form small uniform nanoparticle complexes. Moreover, the ratios of star polymer required to complex siRNA were nontoxic in both pancreatic and lung cancer cells. Treatment with star polymer-siRNA complexes resulted in uptake of siRNA into both cell lines and a significant decrease in target gene mRNA and protein levels. In addition, delivery of clinically relevant amounts of siRNA complexed to the star polymer were able to silence target gene expression by 50% in an in vivo tumor setting. Collectively, these results provide the first evidence of well-defined small cationic star polymers to deliver active siRNA to both pancreatic and lung cancer cells and may be a valuable tool to inhibit key genes involved in promoting chemotherapy drug resistance and metastases.
authors.affiliation: Tumour Biology and Targeting Program, Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, NSW, Australia.
authors.forename: Cyrille
authors.initials: C
authors.lastname: Boyer
authors.forename: Joann
authors.initials: J
authors.lastname: Teo
authors.forename: Phoebe
authors.initials: P
authors.lastname: Phillips
authors.forename: Rafael B
authors.initials: RB
authors.lastname: Erlich
authors.forename: Sharon
authors.initials: S
authors.lastname: Sagnella
authors.forename: George
authors.initials: G
authors.lastname: Sharbeen
authors.forename: Tanya
authors.initials: T
authors.lastname: Dwarte
authors.forename: Hien T T
authors.initials: HT
authors.lastname: Duong
authors.forename: David
authors.initials: D
authors.lastname: Goldstein
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Davis
authors.forename: Maria
authors.initials: M
authors.lastname: Kavallaris
authors.forename: Joshua
authors.initials: J
authors.lastname: McCarroll
mesh_terms: D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002850:Chromatography, Gel; D005260:Female; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D046529:Microscopy, Electron, Transmission; D053758:Nanoparticles / Q000737:chemistry; D011108:Polymers / Q000737:chemistry*; D034741:RNA, Small Interfering / Q000008:administration & dosage*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D011108:Polymers; D034741:RNA, Small Interfering