Systemic siRNA delivery to a spontaneous pancreatic tumor model in transgenic mice by PEGylated calcium phosphate hybrid micelles.

Abstract

Efficient systems for delivery of small interfering RNA (siRNA) are required for clinical application of RNA interference (RNAi) in cancer therapy. Herein, we developed a safe and efficient nanocarrier comprising poly(ethylene glycol)-block-charge-conversional polymer (PEG-CCP)/calcium phosphate (CaP) hybrid micelles for systemic delivery of siRNA and studied their efficacy in spontaneous bioluminescent pancreatic tumors from transgenic mice. PEG-CCP was engineered to provide the siRNA-loaded hybrid micelles with enhanced colloidal stability and biocompatibility due to the PEG capsule and with endosome-disrupting functionality due to the acidic pH-responsive CCP segment where the polyanionic structure could be converted to polycationic structure at acidic pH through cis-aconitic amide cleavage. The resulting hybrid micelles were confirmed to have a diameter of <50nm, with a narrow size distribution. Intravenously injected hybrid micelles significantly reduced the luciferase-based luminescent signal from the spontaneous pancreatic tumors in an siRNA sequence-specific manner. The gene silencing activity of the hybrid micelles correlated with their preferential tumor accumulation, as indicated by fluorescence imaging and histological analysis. Moreover, there were no significant changes in hematological parameters in mice treated with the hybrid micelles. These results demonstrate the great potential of the hybrid micelles as siRNA carriers for RNAi-based cancer therapy.

• Authors: Frederico Pittella, Horacio Cabral, Yoshinori Maeda, Peng Mi, Sumiyo Watanabe, Hiroyasu Takemoto, Hyun Jin Kim, Nobuhiro Nishiyama, Kanjiro Miyata, Kazunori Kataoka
• Journal: Journal of controlled release : official journal of the Controlled Release Society (J Control Release) Vol. 178 Pg. 18-24 (Mar 28 2014) ISSN: 1873-4995 [Electronic] Netherlands
• PMID: 24440662 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier B.V. All rights reserved.

Chemical References

• Calcium Phosphates
• Micelles
• RNA, Small Interfering
• Polyethylene Glycols
• calcium phosphate
• Luciferases

Topics

• Animals
• Calcium Phosphates (chemistry)
• Cell Line, Tumor
• Gene Silencing
• Luciferases (genetics)
• Male
• Mice
• Mice, Transgenic
• Micelles
• Nanoparticles (administration & dosage, chemistry)
• Pancreatic Neoplasms (genetics, metabolism)
• Polyethylene Glycols (chemistry)
• RNA, Small Interfering (administration & dosage, pharmacokinetics)
• Tissue Distribution