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The distribution, clearance, and safety of an anti-MMP-9 DNAzyme in normal and MMTV-PyMT transgenic mice.

Abstract
Catalytic oligonucleotides, known as DNAzymes, are a new class of nucleic acid-based gene therapy that have recently been used in preclinical animal studies to treat various cancers. In this study the systemic distribution, pharmacokinetics, and safety of intravenously administered anti-MMP (matrix metalloproteinase)-9 DNAzyme (AM9D) were determined in healthy FVB and in MMTV-polyoma virus middle T (PyMT) transgenic mice bearing mammary tumors. MMP-9 is known to be involved in tumor cell development, angiogenesis, invasion, and metastasis. Sulfur-35 ((35)S) labeled ([(35)S]-AM9D) administered intravenously, without the use of carrier molecules, to healthy and mammary tumor bearing MMTV-PyMT transgenic mice distributed to all major organs. The order of percentages of [(35)S]-AM9D accumulation in different organs of healthy and MMTV-PyMT mice were blood>liver>kidney>lung>spleen>heart and mammary tumor>blood≈liver>kidney>spleen>lung>heart, respectively. The amount of AM9D accumulated in mammary tumors 2 hours post injection was 0.6% and 0.2% higher than in either blood or liver, respectively, and its rate of initial clearance from mammary tissue was at least 50% slower than the other organs. Approximately 43% of the delivered dosage of [(35)S]-AM9D was cleared from the system via feces and urine over a period of 72 hours. No evidence of acute or chronic cytotoxicity, local or widespread, associated with AM9D treatment (up to 75 mg AM9D /kg of body weight) was observed in the organs examined. These data suggest that DNAzyme in general and AM9D in particular can be used systemically as a therapeutic agent to treat patients with breast cancer or other metastatic and surgically inaccessible tumors.
AuthorsMiranda A Hallett, Pooja Dalal, Trevor W Sweatman, Tayebeh Pourmotabbed
JournalNucleic acid therapeutics (Nucleic Acid Ther) Vol. 23 Issue 6 Pg. 379-88 (Dec 2013) ISSN: 2159-3345 [Electronic] United States
PMID24083396 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Antineoplastic Agents
  • DNA, Catalytic
  • anti-MMP-9 DNAzyme
  • Matrix Metalloproteinase 9
  • Mmp9 protein, mouse
Topics
  • Administration, Intravenous
  • Animals
  • Antineoplastic Agents (administration & dosage, pharmacokinetics, toxicity)
  • DNA, Catalytic (administration & dosage, pharmacokinetics, toxicity)
  • Drug Screening Assays, Antitumor
  • Female
  • Mammary Neoplasms, Experimental (drug therapy, metabolism)
  • Mammary Tumor Virus, Mouse
  • Matrix Metalloproteinase 9 (metabolism)
  • Mice
  • Mice, Transgenic
  • Polyomavirus
  • Tissue Distribution

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