A universal self-delivery lactate metabolism regulating polyprodrug enhances tumor photodynamic therapy

Lactate plays vital roles in promoting immunosuppressive tumor microenvironment, tumor angiogenesis and drug resistance, therefore, lactate modulation is a promising strategy to conquer the restrictions of many therapeutic modalities. A universal drug self-delivery nano-platform with easy synthesis and superior biosafety for lactate regulation is still needed. Herein, alpha-cyano-4-hydroxycinnamic acids (alpha-CHC), as monocarboxylic acid transporter 1 (MCT1) inhibitors, are polycondensed into poly (alpha-cyano-4-hydroxycinnamic acid) (PCHC) for the first time to function as both the lactate metabolism regulation prodrug and a drug carrier of, in this case, photosensitizer Protoporphyrin IX (PpIX). Once triggering by the intracellular esterase, the co-assembled PCHC@PpIX nanoparticles (shorted as PCPp NPs) are degraded accordingly and the generated alpha-CHC monomer inhibits MCT1 to cut down the lactate influx and further reduces endogenous oxygen (O2) loss in tumor cells. By utilizing the elevated O2 level, the released PpIX produces more cytotoxic reactive oxygen species (ROS) and only a single dosage (total PpIX: 0.10 mg per mice) with extremely low light exposure (3.5 J cm-2) is needed for tumor elimination. This work provides a charming lactate metabolic modulating polyprodrug based self-delivery nano-platform for universal hydrophobic drug delivery to improve anticancer efficacy especially for those oxygen dependent therapeutic strategies.