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.
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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.
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ACKNOWLDGEMENTS AND DISCLOSURES
This work was funded by grants from National Natural Science Foundation of China (51173029, 81072595, and 81172995).
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Zhang, J., He, C., Tang, C. et al. Ternary Polymeric Nanoparticles for Oral siRNA Delivery. Pharm Res 30, 1228–1239 (2013). https://doi.org/10.1007/s11095-012-0961-8
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DOI: https://doi.org/10.1007/s11095-012-0961-8