Carrier Free O2-Economizer for Photodynamic Therapy Against Hypoxic Tumor by Inhibiting Cell Respiration

Abnormal tumor metabolism causes the hypoxic microenvironment, which greatly limits the efficacy of photodynamic therapy (PDT). In this work, a strategy of metabolic reprogramming is proposed to economize O-2 for enhanced PDT against hypoxic tumors. The carrier-free O-2-economizer (designated as LonCe) is prepared based on the metabolic antitumor drug of Lonidamine (Lon) and the photosensitizer of chlorin e6 (Ce6). By virtue of intermolecular interactions, Lon and Ce6 self-assemble into nanosized LonCe with favorable stability and high drug contents. Compared with Ce6, LonCe exhibits an improved cellular uptake and photodynamic property for tumor treatment. Moreover, LonCe is capable of inhibiting cell metabolism and mitochondrial respiration to remit the tumor hypoxia, which would promote reactive oxygen species (ROS) production and elevate the PDT efficacy on tumor suppression. In vivo experiments indicate that intravenously injected LonCe prefers to accumulate at the tumor site for highly efficient PDT regardless of the hypoxic environment. Besides, the self-delivery LonCe is fabricated without any carriers, which avoids the excipients induced system toxicity and immunogenicity in vivo. This carrier-free nanomedicine with cell respiratory inhibition mechanism would expedite the development and clinical translation of photodynamic nanoplatforms in tumor treatment.

Automated summary

This study proposes a strategy of metabolic reprogramming to enhance the efficacy of photodynamic therapy (PDT) against hypoxic tumors. The carrier-free O-2-economizer LonCe, consisting of Lonidamine (Lon) and chlorin e6 (Ce6), is capable of inhibiting cell metabolism and mitochondrial respiration to relieve tumor hypoxia and improve the production of reactive oxygen species (ROS) for enhanced PDT efficacy. In vivo experiments demonstrate the high efficiency of intravenously injected LonCe in the hypoxic tumor microenvironment. This carrier-free nanomedicine with a cell respiratory inhibition mechanism could accelerate the development and clinical translation of photodynamic nanoplatforms in tumor treatment.