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Antisense oligonucleotides: target validation and development of systemically delivered therapeutic nanoparticles.

Abstract
Antisense oligonucleotides (ASO) against specific molecular targets (e.g., Bcl-2 and Raf-1) are important reagents in cancer biology and therapy. Phosphorothioate modification of the ASO backbone has resulted in an increased stability of ASO in vivo without compromising, in general, their target selectivity. Although the power of antisense technology remains unsurpassed, dose-limiting side effects of modified ASO and inadequate penetration into the tumor tissue have necessitated further improvements in ASO chemistry and delivery systems. Oligonucleotide delivery systems may increase stability of the unmodified or minimally modified ASO in plasma, enhance uptake of ASO by tumor tissue, and offer an improved therapy response. Here, we provide an overview of ASO design and in vivo delivery systems, and focus on preclinical validation of a liposomal nanoparticle containing minimally modified raf antisense oligodeoxynucleotide (LErafAON). Intact rafAON (15-mer) is present in plasma and in normal and tumor tissues of athymic mice systemically treated with LErafAON. Raf-1 expression is decreased in normal and tumor tissues of LErafAON-treated mice. Therapeutic benefit of a combination of LErafAON and radiation or an anticancer drug exceeds radiation or drug alone against human prostate, breast, and pancreatic tumors grown in athymic mice. Further improvements in ASO chemistry and nanoparticles are promising avenues in antisense therapy of cancer.
AuthorsChuanbo Zhang, Jin Pei, Deepak Kumar, Isamu Sakabe, Howard E Boudreau, Prafulla C Gokhale, Usha N Kasid
JournalMethods in molecular biology (Clifton, N.J.) (Methods Mol Biol) Vol. 361 Pg. 163-85 ( 2007) ISSN: 1064-3745 [Print] United States
PMID17172711 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Review)
Chemical References
  • Antineoplastic Agents
  • Drug Carriers
  • LErafAON
  • Oligodeoxyribonucleotides
  • Oligonucleotides, Antisense
  • Proto-Oncogene Proteins c-bcl-2
  • Thionucleotides
  • oblimersen
  • Proto-Oncogene Proteins c-raf
Topics
  • Animals
  • Antineoplastic Agents (chemistry, pharmacology, therapeutic use)
  • Combined Modality Therapy
  • Disease Models, Animal
  • Drug Carriers (chemistry, pharmacology, therapeutic use)
  • Gene Expression Regulation, Neoplastic (drug effects, genetics)
  • Humans
  • Mice
  • Mice, Nude
  • Nanoparticles (therapeutic use)
  • Neoplasms (drug therapy, genetics, metabolism)
  • Oligodeoxyribonucleotides (chemistry, genetics, pharmacology, therapeutic use)
  • Oligonucleotides, Antisense (chemistry, genetics, pharmacology, therapeutic use)
  • Proto-Oncogene Proteins c-bcl-2 (antagonists & inhibitors, biosynthesis, genetics)
  • Proto-Oncogene Proteins c-raf (antagonists & inhibitors, biosynthesis, genetics)
  • Thionucleotides (chemistry, genetics, pharmacology, therapeutic use)

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