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.