Low-irradiance PDT enhances tumor accumulation of 2ME-based nano-prodrug to achieve metastasis inhibition via HIF-1 suppression

The degree of vascular leakiness within tumor tissues varies according to origins, phases, and organs of the malignancies. As a result, nano-prodrugs may suffer inadequate tumor accumulation due to limited vascular permeability. To address this issue, we developed 2ME-Ppa as a nano-prodrug to enhance vessel permeability at the tumor site via low-irradiance photodynamic therapy (PDT). In the nano-prodrug, 2-methoxyestradiol (2ME) was utilized as an antitumor drug to inhibit tumor growth and simultaneously it acted as an inhibitor to suppress the expression of hypoxia-inducible factor-1 alpha (HIF-1 alpha), thereby reducing the risk of tumor metastasis. In a bilateral 4 T1 tumor xenograft model, the tumor exposed to low-irradiance PDT exhibited a higher level of nano-prodrug accumulation compared to the unirradiated one, which was confirmed by fluorescence imaging and magnetic resonance imaging (MRI). This increased nano-prodrug accumulation correlated with a significant reduction in average tumor volume, measured from a traditional method and the reconstructed 3D tumor images of MRI scans. The 2ME-Ppa-treated mice showed a reduced number of lung metastasis compared with the control group without 2ME in the small animal Micro CT images or HE-stained pathological sections. Thus, the combination of PDT-enhanced vascular permeability and 2ME-induced HIF-1 alpha inhibition may become a novel and potent tumor treatment method.