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

Miranda A. Hallett, Pooja Dalal, Trevor W. Sweatman, Tayebeh Pourmotabbed

Research output: Contribution to journalArticle

7 Citations (Scopus)

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 (35S) labeled ([35S]-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 [35S]-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 [35S]-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.

Original languageEnglish (US)
Pages (from-to)379-388
Number of pages10
JournalNucleic Acid Therapeutics
Volume23
Issue number6
DOIs
StatePublished - Dec 1 2013

Fingerprint

Catalytic DNA
Polyomavirus
Viruses
Transgenic Mice
Matrix Metalloproteinase 9
Safety
Tumors
Breast Neoplasms
Bearings (structural)
Matrix Metalloproteinases
Liver
Blood
Spleen
anti-MMP-9 DNAzyme
Kidney
Gene therapy
Neoplasms
Lung
Heart Neoplasms
Pharmacokinetics

All Science Journal Classification (ASJC) codes

  • Genetics
  • Molecular Biology
  • Molecular Medicine
  • Biochemistry
  • Drug Discovery

Cite this

The distribution, clearance, and safety of an anti-MMP-9 DNAzyme in normal and MMTV-PyMT transgenic mice. / Hallett, Miranda A.; Dalal, Pooja; Sweatman, Trevor W.; Pourmotabbed, Tayebeh.

In: Nucleic Acid Therapeutics, Vol. 23, No. 6, 01.12.2013, p. 379-388.

Research output: Contribution to journalArticle

Hallett, Miranda A. ; Dalal, Pooja ; Sweatman, Trevor W. ; Pourmotabbed, Tayebeh. / The distribution, clearance, and safety of an anti-MMP-9 DNAzyme in normal and MMTV-PyMT transgenic mice. In: Nucleic Acid Therapeutics. 2013 ; Vol. 23, No. 6. pp. 379-388.
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