Inhibiting Stress‐Activated Signals to Reverse Heat Resistance for Augmented Photothermal Therapy Based on Biologically Derived Nanotherapeutics

Abstract

AbstractSeveral stress‐activated signals are highly responsible for the thermal tolerance and attribute to the poor therapeutic outcome of photothermal therapy (PTT). In this study, the naturally human hair‐derived nanoparticles (Hair NPs) with significant photothermal conversion efficacy are explored to combine with stress‐activated signal inhibitors for maximizing the PTT efficiency. During the Hair NPs‐based PTT, two distinct signals are found to be remarkably upregulated. One is the heat‐induced overexpression of HSP90, and the other one is the activation of mitogen‐activated protein kinase (MAPK) signaling pathway. Through the integration of particular inhibitors (17‐allylamino‐17‐demethoxygeldanamycin (17AAG) specifically binding to HSP90 or LY2228820 targeting to p38 MAPK) and the subsequent modification of hyaluronic acid (HA), the resultant Hair NPs‐HA@inhibitor can specifically deliver the inhibitor into tumor cells with minimal side effects on normal tissues, which can specifically block the stressfully activated signals as well as inhibit the expression of their downstream effectors (e.g., MMPs, VEGF) that are closely related with tumor survival and invasion. Without these elements to protect tumor cells or promote tumor progression, the Hair NPs‐induced PTT effect can be much elevated, resulting in a superior antitumor efficacy. These findings represent an effective approach in maximizing PTT effect for fighting against tumor.