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wnloade pose: Atu027, a novel RNA interference therapeutic, has been shown to inhibit lymph node tasis in orthotopic prostate cancer mouse models. The aim of this study is to elucidate the acologic activity of Atu027 in inhibiting hematogenous metastasis to the target organ lung in four nt preclinical mouse models. erimental Design: Atu027 compared with vehicle or control small interfering RNA lipoplexes was in two experimental lung metastasis models (Lewis lung carcinoma, B16V) and spontaneous tasis mouse models (MDA-MB-435, MDA-MB-231, mammary fat pad). Different dosing schedules ted low volume tail vein injections) were applied to obtain insight into effective Atu027 treatment. ry tumor growth and lung metastasis were measured, and tissues were analyzed by immunohistostry and histology. In vitro studies in human umbilical vein endothelial cells were carried out to e an insight into molecular changes on depletion of PKN3, in support of efficacy results. ults: Intravenous administration of Atu027 prevents pulmonary metastasis. In particular, formaf spontaneous lung metastasis was significantly inhibited in animals with large tumor grafts as well mice with resected primary mammary fat pad tumors. In addition, we provide evidence that an se in VE-cadherin protein levels as a downstream result of PKN3 target gene inhibition may change helial function, resulting in reduced colonization and micrometastasis formation. clusion: Atu027 can be considered as a potent drug for preventing lung metastasis formation, Con which might be suitable for preventing hematogenous metastasis in addition to standard cancer therapy.