Coordinating the Mechanisms of Action of Ferroptosis and the Photothermal Effect for Cancer Theranostics

Abstract

Combination therapy based on different mechanisms of cell death has shown promise in tumor therapy. However, when different modalities are integrated, the maximum synergy of the therapeutic effects is often lacking in the design. Herein, we report a cancer theranostic nanomedicine formula developed by considering the mechanisms of action of ferroptosis and the photothermal effect in combination therapy. The croconaine molecule was encapsulated as both a photothermal converter and an iron‐chelating agent with BSA, thus leading to biocompatible and stable Cro‐Fe@BSA nanoparticles (NPs). The Cro‐Fe@BSA NPs in the tumor milieu showed an activated photothermal effect leading to enhanced radical formation owing to the temperature‐dependent Fenton reaction kinetics, while radical formation during ferroptosis in turn prevented the heat‐induced formation of heat shock proteins and thus the self‐protection mechanism of cancer cells in response to heat. The activatable photoacoustic and magnetic resonance imaging performance of the Cro‐Fe@BSA NPs also enabled safe and reliable cancer theranostics.

Tumor‐specific and photothermal‐augmented chemodynamic therapy by ferrocene‐carbon dot‐crosslinked nanoparticles

“…Besides, the FL intensity of TA probe also increased with prolonged laser irradiation time (Figure 2H), further confirming the heat‐augmented • OH generation of Fc‐CD NPs. Interestingly, the therapeutic efficiency of PTT was known to be restricted by thermoresistance arising from the expression of HSPs, 24,43 but it has been reported that upregulated ROS level was able to inhibit the HSPs expression 24,25 . Thus, the produced • OH could in turn overcome the inherent drawbacks of conventional PTT and result in multibenefit treatment outcomes.…”

“…Interestingly, the therapeutic efficiency of PTT was known to be restricted by thermoresistance arising from the expression of HSPs, 24,43 but it has been reported that upregulated ROS level was able to inhibit the HSPs expression. 24,25 Thus, the produced • OH could in turn overcome the inherent drawbacks of conventional PTT and result in multibenefit treatment outcomes. Taken together, the synergistic heat and • OH generation capabilities of Fc-CD NPs were clearly confirmed, which are beneficial for achieving tumor-specific and enhanced synergistic therapy.…”

“…22,23 Unfortunately, the efficacy of PTT is generally restricted by limited tissue penetration depth of external light and thermoresistance resulting from the elevated expression of heat-shock proteins (HSPs). Interestingly, there are evidence showing that reactive oxygen species (ROS) generation during the chemodynamic therapy (CDT) process could inhibit the upregulation of HSPs via an oxidation manner, 17,24,25 subsequently conquering the thermoresistance of conventional PTT and thus amplifying the hyperthermia treatment efficiency. Notably, as an emerging therapeutic strategy, CDT induces apoptosis utilizing specific chemical reactions activated by specific endogenous stimulus (e.g., overexpressed H 2 O 2 in tumor microenvironment [TME]), which gets rid of the restriction of tissue penetration depth.…”

Industrialization’s eye view on theranostic nanomedicine

“…In addition, the PTT effect could amplify the Fenton reaction to form hydroxyl radicals and a labile iron pool. These cooperative effects constituted MR and PA imaging, ferroptosis, and PTT for cancer theranostics (Zeng et al, 2022). Chuang et al developed and used Y 2 O 3 :Eu@SiO 2 as a nanoscintillator for X-ray activated photodynamic therapy (PDT) in deep cancer theranostics.…”

Synergistic hydroxyl radical formation, system XC- inhibition and heat shock protein crosslinking tango in ferrotherapy: A prove-of-concept study of “sword and shield” theory

“…In this regard, HSPs was considered as the negative regulator of ferroptosis, and HSPs inhibition increases the efficiency of ferroptosis. It has been reported that the primary amines of HSPs could be cross-linked by ROS or LPO ending products [ 13 , 14 ].…”