1 research outputs found
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
(<i>TUBB3</i>/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