Antitumor activity of small interfering RNA/cationic liposome complex in mouse models of cancer
Junichi Yano1, Kazuko Hirabayashi, Shin-Ichiro Nakagawa
1Discovery Research Laboratories, Nippon Shinyaku Co, Ltd., Kyoto, Japan; and Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan. j.yano@po.nippon-shinkayu.co.jp
Purpose:
The RNA interference effect is an alternative to antisense DNA as an experimental method of down-regulating a specific target protein. Although the RNA interference effect, which is mediated by small interfering RNA (siRNA) or micro-RNA, has potential application to human therapy, the hydrodynamic method usually used for rapid administration of oligonucleotides is unsuitable for use in humans. In this study, we have investigated the antitumor activity of a synthetic siRNA, B717, which is sequence specific for the human bcl-2 oncogene, complexed with a novel cationic liposome, LIC-101.
Experimental Design:
In a mouse model of liver metastasis, we administered B717/LIC-101 by bolus intravenous injection, adjusting the rate and volume of administration to what is feasible in human therapy. In a mouse model bearing prostate cancer in which the cells were inoculated under the skin, B717/LIC-101 was administered subcutaneously around the tumor.
Results:
The B717/LIC-101 complex inhibited the expression of bcl-2 protein and the growth of tumor cell lines in vitro in a sequence-specific manner in the concentration range of 3 to 100 nmol/L. Furthermore, the complex had a strong antitumor activity when administered intravenously in the mouse model of liver metastasis. B717 (siRNA) was shown to be delivered to tumor cells in the mouse liver, but only when complexed with LIC-101. The complex also inhibited tumor cell growth in the mouse model bearing prostate cancer.
Conclusions:
By combining siRNA with our cationic liposome, we overcame the difficulty of administering siRNA to animals in ways that can be applied in human therapy. Although our siRNA/liposome complex is not yet in clinical trials, it is expected to provide a novel siRNA therapy for cancer patients.
Insights
This study shows that a novel liposome complex (LIC-101) effectively delivers small interfering RNA (siRNA) to inhibit cancer growth. This approach offers a promising new method for siRNA cancer therapy applicable to humans.
Area of Science:
- Molecular Biology
- Oncology
- Drug Delivery Systems
Background:
- RNA interference (RNAi) offers a method for down-regulating specific target proteins.
- Small interfering RNA (siRNA) mediates RNAi but faces challenges in human therapeutic administration.
- Hydrodynamic delivery methods for oligonucleotides are not suitable for human therapy.
Purpose of the Study:
- To investigate the antitumor activity of a synthetic siRNA (B717) targeting the human bcl-2 oncogene.
- To evaluate the efficacy of B717 complexed with a novel cationic liposome (LIC-101).
- To assess the feasibility of siRNA administration methods for human therapy.
Main Methods:
- Administered B717/LIC-101 via intravenous and subcutaneous injections in mouse models.
- Utilized mouse models for liver metastasis and subcutaneous prostate cancer.
- Adjusted administration rates and volumes to simulate human therapeutic conditions.
Main Results:
- B717/LIC-101 complex inhibited bcl-2 protein expression and tumor cell growth in vitro.
- Demonstrated significant antitumor activity in a mouse model of liver metastasis.
- Confirmed successful delivery of siRNA to tumor cells in the liver when complexed with LIC-101.
- Showed inhibition of tumor cell growth in a prostate cancer mouse model.
Conclusions:
- Combining siRNA with LIC-101 overcomes challenges in siRNA administration for potential human therapy.
- The developed siRNA/liposome complex shows promise as a novel cancer therapy.
- Further development is expected to lead to clinical applications for cancer patients.
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