A rationally optimized nanoparticle system for the delivery of RNA interference therapeutics into pancreatic tumors in vivo

Joann Teo, Joshua A. McCarroll, Cyrille Boyer, Janet Youkhana, Sharon M. Sagnella, Hien T. T. Duong, Jie Liu, George Sharbeen, David Goldstein, Thomas P. Davis, Maria Kavallaris, Phoebe A. Phillips

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Pages (from-to)2337-2351
Number of pages15
JournalBiomacromolecules
Volume17
Issue number7
DOIs
Publication statusPublished - 11 Jul 2016

Cite this

Teo, J., McCarroll, J. A., Boyer, C., Youkhana, J., Sagnella, S. M., Duong, H. T. T., ... Phillips, P. A. (2016). A rationally optimized nanoparticle system for the delivery of RNA interference therapeutics into pancreatic tumors in vivo. Biomacromolecules, 17(7), 2337-2351. https://doi.org/10.1021/acs.biomac.6b00185
Teo, Joann ; McCarroll, Joshua A. ; Boyer, Cyrille ; Youkhana, Janet ; Sagnella, Sharon M. ; Duong, Hien T. T. ; Liu, Jie ; Sharbeen, George ; Goldstein, David ; Davis, Thomas P. ; Kavallaris, Maria ; Phillips, Phoebe A. / A rationally optimized nanoparticle system for the delivery of RNA interference therapeutics into pancreatic tumors in vivo. In: Biomacromolecules. 2016 ; Vol. 17, No. 7. pp. 2337-2351.
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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.",
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Teo, J, McCarroll, JA, Boyer, C, Youkhana, J, Sagnella, SM, Duong, HTT, Liu, J, Sharbeen, G, Goldstein, D, Davis, TP, Kavallaris, M & Phillips, PA 2016, 'A rationally optimized nanoparticle system for the delivery of RNA interference therapeutics into pancreatic tumors in vivo' Biomacromolecules, vol. 17, no. 7, pp. 2337-2351. https://doi.org/10.1021/acs.biomac.6b00185

A rationally optimized nanoparticle system for the delivery of RNA interference therapeutics into pancreatic tumors in vivo. / Teo, Joann; McCarroll, Joshua A.; Boyer, Cyrille; Youkhana, Janet; Sagnella, Sharon M.; Duong, Hien T. T.; Liu, Jie; Sharbeen, George; Goldstein, David; Davis, Thomas P.; Kavallaris, Maria; Phillips, Phoebe A.

In: Biomacromolecules, Vol. 17, No. 7, 11.07.2016, p. 2337-2351.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - A rationally optimized nanoparticle system for the delivery of RNA interference therapeutics into pancreatic tumors in vivo

AU - Teo, Joann

AU - McCarroll, Joshua A.

AU - Boyer, Cyrille

AU - Youkhana, Janet

AU - Sagnella, Sharon M.

AU - Duong, Hien T. T.

AU - Liu, Jie

AU - Sharbeen, George

AU - Goldstein, David

AU - Davis, Thomas P.

AU - Kavallaris, Maria

AU - Phillips, Phoebe A.

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AB - 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.

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U2 - 10.1021/acs.biomac.6b00185

DO - 10.1021/acs.biomac.6b00185

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