Thermal Stimuli-Responsive Nanoplatform Based on Phase Change Material for Synergistic Enhancement of p53 Protein Expression in HCC

Abstract TP53 is one of the most important tumor suppressor genes and is known as the “genetic guardian”. Targeting the MDM2-p53 loop is an attractive tumor treatment strategy. Herein, an organic PCM with a melting point of 43.5℃ was prepared by using biocompatible fatty acids and alcohols. PCM was used to co-encapsulate a photosensitizer (IR780) and a novel MDM2-p53 inhibitor (APG-115). The final prepared multifunctional temperature responsive release nanoplatform (PIA NPs) can not only effectively deliver APG-115 and IR780 but also act as a “gatekeeper” to protect the delivered drug, avoid hydration of IR780, and prevent drug leakage. Under 808 nm laser irradiation, the protected IR780 can melt the PCM by generating the photothermal effect, thereby achieving drug release regulated by exogenous stimuli (light). Furthermore, the oxidative stress signal (ROS) generated by the PDT effect of IR780 can promote the expression of p53 protein, collaborating with APG-115 to improve the therapeutic efficiency of HCC. PIA NPs have shown superior therapeutic effects in vivo and vitro. This PDT/PTT/MDM2-p53 inhibitor combined therapy strategy provides an unprecedented approach to the treatment of HCC via synergistically enhancing p53 expression.