The distribution, clearance, and safety of an anti-MMP-9 DNAzyme in normal and MMTV-PyMT transgenic mice.
The distribution, clearance, and safety of an anti-MMP-9 DNAzyme in normal and MMTV-PyMT transgenic mice.
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DOI：
10.1089/nat.2012.0348
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发表时间：
2013-12
影响因子：
4
通讯作者：
M. Hallett;P. Dalal;T. Sweatman;T. Pourmotabbed
中科院分区：
文献类型：
--
作者：
M. Hallett;P. Dalal;T. Sweatman;T. Pourmotabbed
催化寡核苷酸，又称DNAzyme，是一种新型的基于核酸的基因治疗方法，最近已被用于临床前动物研究，以治疗各种癌症。本研究测定了静脉注射抗基质金属蛋白酶-9脱氧核酶(AM9D)在健康FVB和MMTV-多瘤病毒中T(PYMT)转基因小鼠体内的分布、药代动力学和安全性。已知基质金属蛋白酶-9参与肿瘤细胞的发育、血管生成、侵袭和转移。[(35)S]标记的硫-35([(35)S]-AM9D)在不使用载体分子的情况下，静脉注射给健康和乳腺癌MMTV-PYMT转基因小鼠，分布于各主要器官。[(35)S]-AM9D在健康小鼠和MMTV-PYMT小鼠不同器官中的蓄积百分率依次为blood>；liver>；kidney>；lung>；spleen>；heart和乳房tumor>；blood≈liver>；kidney>；spleen>；lung>；heart，。注射后2小时，AM9D在乳腺肿瘤中的蓄积量分别比血液和肝脏高0.6%和0.2%，其从乳腺组织的初始清除速度至少比其他器官慢50%。在72小时内，大约43%的[(35)S]-AM9D通过粪便和尿液从系统中被清除。在被检查的器官中没有观察到与AM9D治疗(高达75 mg AM9D/公斤体重)有关的急性或慢性细胞毒性的证据，无论是局部的还是广泛的。这些数据表明，DNAzyme，特别是AM9D可以系统地用作治疗乳腺癌或其他转移性和手术无法触及的肿瘤的药物。
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.