Tumor regression in mice by delivery of Bcl-2 small interfering RNA with pegylated cationic liposomes
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Satoru Sonoke1, Toshihiro Ueda, Kae Fujiwara
1Discovery Research Laboratories, Nippon Shinyaku Co Ltd, Tsukuba, Japan. s.sonoke@po.nippon-shinyaku.co.jp
Abstract:
The pharmacokinetics and antitumor activity of pegylated small interfering RNA (siRNA)/cationic liposome complexes were studied after systemic administration to mice. We designed pegylated-lipid carriers for achieving increased plasma concentrations of RNA and hence improved accumulation of RNA in tumors by the enhanced permeability and retention effect. We compared the pharmacokinetics of siRNA complexed with liposomes incorporating pegylated lipids with longer (C-17 or C-18), shorter (C-12 to C-16), or unsaturated (C-18:1) acyl chains. When longer acyl chains were used, the plasma concentrations of siRNA obtained were dramatically higher than when shorter or unsaturated chains were used. This may be explained by the higher gel-to-liquid-crystalline phase-transition temperature (Tc) of lipids with longer acyl chains, which may form more rigid liposomes with reduced uptake by the liver. We tested a siRNA that is sequence specific for the antiapoptotic bcl-2 mRNA complexed with a pegylated liposome incorporating a C-18 lipid (PEG-LIC) by i.v. administration in a mouse model of human prostate cancer. Three-fold higher accumulation of RNA in the tumors was achieved when PEG-LIC rather than nonpegylated liposomes was used, and sequence-specific antitumor activity was observed. Our siRNA/PEG-LIC complex showed no side effects on repeated administration and the strength of its antitumor activity may be attributed to its high uptake by the tumors. Pegylation of liposomes improved the plasma retention, uptake by s.c. tumors, and antitumor activity of the encapsulated siRNA. PEG-LIC is a promising candidate for siRNA cancer therapy.
Insights
Pegylated liposomes significantly enhanced the delivery and accumulation of small interfering RNA (siRNA) in tumors. This improved RNA delivery resulted in effective, sequence-specific antitumor activity with no observed side effects in a preclinical cancer model.
Area of Science:
- Nanotechnology in drug delivery
- Molecular biology and genetics
- Oncology and cancer therapeutics
Background:
- Systemic administration of small interfering RNA (siRNA) faces challenges in achieving sufficient plasma concentrations and tumor accumulation.
- Pegylated liposomes are designed to improve drug delivery by leveraging the enhanced permeability and retention (EPR) effect.
Purpose of the Study:
- To investigate the pharmacokinetics and antitumor activity of pegylated siRNA/cationic liposome complexes.
- To evaluate the impact of different acyl chain lengths in pegylated lipids on siRNA delivery and efficacy.
Main Methods:
- Systemic administration of pegylated small interfering RNA (siRNA)/cationic liposome complexes in mice.
- Comparison of siRNA pharmacokinetics with liposomes containing pegylated lipids with varying acyl chain lengths (C-17/C-18, C-12-C-16, C-18:1).
- Evaluation of a specific siRNA targeting bcl-2 mRNA complexed with a pegylated liposome (PEG-LIC) in a prostate cancer mouse model.
Main Results:
- Liposomes with longer acyl chains (C-17, C-18) resulted in dramatically higher plasma concentrations of siRNA compared to shorter or unsaturated chains.
- Pegylated liposomes (PEG-LIC) achieved three-fold higher RNA accumulation in tumors compared to nonpegylated liposomes.
- Sequence-specific antitumor activity was observed with the siRNA/PEG-LIC complex, with no side effects upon repeated administration.
Conclusions:
- Pegylation of liposomes enhances plasma retention, tumor uptake, and antitumor activity of encapsulated siRNA.
- The PEG-LIC complex demonstrates promising potential for siRNA-based cancer therapy due to improved delivery and efficacy.
- Liposome rigidity, influenced by acyl chain length and phase-transition temperature, plays a role in reduced liver uptake and improved pharmacokinetics.
