Summary
By virtue of their potential to selectively silence oncogenic molecules in cancer cells, antisense oligonucleotides (ASO) and small interfering RNAs (siRNAs) are powerful tools for development of tailored anti-cancer drugs. The clinical benefit of ASO/siRNA therapeutic is, however, hampered due to poor pharmacokinetics and biodistribution, and suboptimal suppression of the target in tumor tissues. Raf-1 protein serine/threonine kinase is a druggable signaling molecule in cancer therapy. Our laboratory has developed cationic liposomes for systemic delivery of raf ASO (LErafAON) and raf siRNA (LErafsiRNA) to human tumor xenografts grown in athymic mice. LErafAON is also the first ASO containing liposomal drug tested in humans. In this article, we primarily focus on a modified formulation of systemically delivered cationic liposomes containing raf antisense oligonucleotide (md-LErafAON). The cationic liposomes were prepared using dimyristoyl 1,2-diacyl-3-trimethylammonium-propane (DMTAP), phosphatidylcholine (PC), and cholesterol (CHOL). The toxicology, pharmacokinetics, biodistribution, target selectivity, and anti-tumor efficacy studies of md-LErafAON were conducted in mice. We demonstrate that md-LErafAON is the next generation of systemically delivered and well-tolerated antisense therapeutic suitable for clinical evaluation.
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Acknowledgments
We thank Dr. Lisa Portnoy, Ms. Laura Rutter-Call, Ms. Carrie Silver, and Ms. Amy Durham for technical assistance, and our colleagues and collaborators for their comments. PC-3 cells were obtained from the Tissue Culture Shared Resource, and microscopy was performed at the Microscopy Shared Resource of the Lombardi Comprehensive Cancer Center, Georgetown University Medical Center. Mice clinical pathology and histopathology tests were performed by ANTECH Diagnostics, and data evaluated by a board-certified veterinary pathologist (Pathology Associates International). The liposomal formulation and its use presented in this study are patented (United States patent #s 6126965, 6333314, 6559129, and 7262173). The research work was supported by grants from the National Institutes of Health and NeoPharm, Inc.
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Zhang, C., Newsome, J.T., Mewani, R., Pei, J., Gokhale, P.C., Kasid, U.N. (2009). Systemic Delivery and Pre-clinical Evaluation of Nanoparticles Containing Antisense Oligonucleotides and siRNAs. In: Belting, M. (eds) Macromolecular Drug Delivery. Methods in Molecular Biology, vol 480. Humana Press. https://doi.org/10.1007/978-1-59745-429-2_5
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DOI: https://doi.org/10.1007/978-1-59745-429-2_5
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