Pharmaceutical Research

, Volume 30, Issue 5, pp 1228–1239

Ternary Polymeric Nanoparticles for Oral siRNA Delivery

Research Paper

DOI: 10.1007/s11095-012-0961-8

Cite this article as:
Zhang, J., He, C., Tang, C. et al. Pharm Res (2013) 30: 1228. doi:10.1007/s11095-012-0961-8

ABSTRACT

Purpose

Poor stability and inefficient absorption in the intestinal tract are major barriers confronting oral delivery of siRNA. We aimed to uncover if ternary polymeric nanoparticles (cationic polymer/siRNA/anionic component) can overcome these obstacles through changing the formulation-related parameters.

Methods

Ternary polymeric nanoparticles were prepared by ionic gelation of chitosan, N-trimethyl chitosan (TMC), or thiolated trimethyl chitosan (TTMC) with tripolyphosphate (TPP) or hyaluronic acid (HA), and siRNA was simultaneously encapsulated. Structural stabilities and siRNA protection of these nanoparticles were assessed in simulated intestinal milieu. Their transport across ex vivo rat ileum, macrophage uptake, in vitro gene silencing, and in vivo biodistribution after oral administration were investigated.

Results

Ternary polymeric nanoparticles formed by TTMC, siRNA, and TPP (TTMC/siRNA/TPP nanoparticles) showed suitable structural stability and siRNA protection in the intestinal tract, good permeability across ex vivo rat ileum, superior cellular uptake and gene silencing efficiency in Raw 264.7 cells, and high systemic biodistribution after oral administration.

Conclusions

TTMC/siRNA/TPP nanoparticles demonstrated efficient gene silencing in vitro and systemic biodistribution in vivo, therefore, they were expected to be potential vehicles for oral siRNA delivery.

KEY WORDS

biodistribution gene silencing oral delivery polymeric nanoparticles siRNA 

ABBREVIATIONS

CF

colonic fluids

CMH

colonic mucosa homogenates

CTH

colonic tissue homogenates

DF

duodenal fluids

DMH

duodenal mucosa homogenates

DTH

duodenal tissue homogenates

FAM-NC siRNA

FAM-labeled NC siRNA

HA

hyaluronic acid

IF

ileal fluids

IMH

ileal mucosa homogenates

ITH

ileal tissue homogenates

JF

jejunal fluids

JMH

jejunal mucosa homogenates

JTH

jejunal tissue homogenates

LPS

lipopolysaccharide

NC siRNA

negative control siRNA

RNAi

RNA interference

Scr

scrambled siIL-6

siIL-6

interleukin-6 siRNA

siRNA

small interfering RNA

TAMRA-NC siRNA

TAMRA-labeled NC siRNA

TMC

N-trimethyl chitosan

TPP

tripolyphosphate

TTMC

thiolated trimethyl chitosan.

Supplementary material

11095_2012_961_MOESM1_ESM.doc (1 mb)
ESM 1(DOC 1.02 MB)

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.State Key Laboratory of Genetic Engineering Department of Pharmaceutical Sciences, School of Life SciencesFudan UniversityShanghaiChina

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