Self-remedied Nanomedicine for Surmounting the Achilles's Heel of Photodynamic Tumor Therapy

Abstract Background: Photodynamic therapy (PDT) has been recognized as a promising tumor treatment for its minimal invasiveness, low side effects and on-demand light controllability. However, the oxygen-dependent PDT could exacerbate tumor hypoxia to upregulate the expression of hypoxia-inducible factor-1α (HIF-1α), which would promote tumor growth and metastasis. Inhibition of HIF-1α activity is very necessary to PDT for effective tumor suppression.Results: Herein, we developed a self-remedied nanomedicine based on a photosensitizer and a HIF-1α inhibitor to surmount the Achilles' heel of PDT for enhanced antitumor efficacy. Specifically, the nanomedicine (designated as CYC-1) was prepared by the self-assembly of Ce6 and YC-1 through π-π stacking and hydrophobic interactions. Carrier-free CYC-1 held an extremely high drug loading rate, uniform size distribution and favorable stability. Compared with free Ce6, CYC-1 exhibited an improved cellular uptake behavior and an enhanced ROS production capability. Besides, CYC-1 had the overwhelming superiority on restraining tumor proliferation over the combined administration of Ce6 and YC-1. More importantly, CYC-1 preferred to accumulate in tumor tissue for efficient PDT by inhibiting the activity of HIF-1α. Ultimately, this YC-1-assistant PDT effectively restrained the tumor growth and caused a low system toxicity. Conclusions: This carrier-free self-remedied strategy overcame the Achilles' heel of PDT on tumor suppression while induced a minimal side effect, which would expedite the development and clinical translation of nanomedicine for PDT against hypoxic tumors.