Macromolecular Drug Delivery

Volume 480 of the series Methods in Molecular Biology pp 65-83


Systemic Delivery and Pre-clinical Evaluation of Nanoparticles Containing Antisense Oligonucleotides and siRNAs

  • Chuanbo ZhangAffiliated withDepartments of Radiation Medicine and Biochemistry, Molecular and Cellular Biology, Georgetown University Medical Center
  • , Joseph T. Newsome
  • , Rajshree Mewani
  • , Jin Pei
  • , Prafulla C. Gokhale
  • , Usha N. Kasid

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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.

Key Words

Raf-1 Antisense oligonucleotide siRNA Cationic liposomes Dimyristoyl 1,2-diacyl-3-trimethylammonium-propane (DMTAP) Systemic delivery Toxicology Pharmacokinetics and biodistribution Ionizing radiation Prostate cancer