An Acidity‐Unlocked Magnetic Nanoplatform Enables Self‐Boosting ROS Generation through Upregulation of Lactate for Imaging‐Guided Highly Specific Chemodynamic Therapy

Abstract

Chemodynamic therapy is an emerging tumor therapeutic strategy. However, the anticancer effects are greatly limited by the strong acidity requirements for effective Fenton‐like reaction, and the inevitably “off‐target” toxicity. Herein, we develop an acidity‐unlocked nanoplatform (FePt@FeOx@TAM‐PEG) that can accurately perform the high‐efficient and tumor‐specific catalysis for anticancer treatment, through dual pathway of cyclic amplification strategy. Notably, the pH‐responsive peculiarity of tamoxifen (TAM) drug allows for the catalytic activity of FePt@FeOx to be “turn‐on” in acidic tumor microenvironments, while keeping silence in neutral condition. Importantly, the released TAM within cancer cells is able to inhibit mitochondrial complex I, leading to the upregulated lactate content and thereby the accumulated intracellular H+, which can overcome the intrinsically insufficient acidity of tumor. Through the positive feedback loop, large amount of active FePt@FeOx nanocatalyzers are released and able to access to the endogenous H2O2, exerting the improved Fenton‐like reaction within the more acidic condition. Finally, such smart nanoplatform enables self‐boosting generation of reactive oxygen species (ROS) and induces strong intracellular oxidative stress, leading to the substantial anticancer outcomes in vivo, which may provide a new insight for tumor‐specific cascade catalytic therapy and reducing the “off‐target” toxicity to surrounding normal tissues.

Manipulating Intratumoral Fenton Chemistry for Enhanced Chemodynamic and Chemodynamic‐Synergized Multimodal Therapy

“…Therefore, some adjuvant treatment strategies have been proposed to speed up Fenton/Fenton‐like reactions and increase ROS accumulation in tumor cells, thereby amplifying the CDT effect. [ 120 ] Among the developed strategies, three kinds of ROS‐involving therapy modalities by external energy‐field stimulation, including radiotherapy, [ 121 ] photodynamic therapy (PDT), [ 122 ] and sonodynamic therapy (SDT), [ 123 ] have been applied in combination with ECDT to achieve tumor ablation through highly efficient production of ROS. In this design, the external energy fields, including light, heat, ultrasound, magnetism, and electric field can facilitate intratumoral Fenton/Fenton‐like reaction and achieve ECDT effect.…”

Recent advances of cancer chemodynamic therapy based on Fenton/Fenton-like chemistry

“…4a), which could be used for H + self-accumulated cancer chemodynamic therapy derived by heterogeneous Fenton/Fenton-like reaction with boosting catalytic efficiency. 44 As shown in Fig. 4b-f, FePt@FeO x @TAM-PEG NP exhibited a better ROS generation ability under the same pH condition compared with FePt@FeO x -PEG because of the self-supplied H + by TAM, thus achieving a better chemodynamic therapeutic performance in cell assays (Fig.…”

Nanocatalyst‐Mediated Chemodynamic Tumor Therapy

“…[84,85] Therefore, adjusting the pH values in tumors is an alternative strategy to enhance the reaction efficiency. [86] GOx can consume glucose and oxygen to generate gluconic acid and H 2 O 2 , [87] which has been applied to increase H 2 O 2 level and elevate acidity in TME. [88][89][90] Thus, GOx have been widely led into the CDT-based therapeutic strategies to realize a satisfied antitumor effect.…”

“…Similarly, Guo et al designed a nanocatalyst (FePt@FeOx@TAM-PEG), which could controllably regulate the acidic conditions at the tumor site for enhanced CDT. [86] The catalytic activity of FePt@FeOx was "turn-on" in an acidic microenvironment with help of the pH-responsive peculiarity of tamoxifen (TAM) drug. More importantly, once TAM entered the cancer cells, it would lead to the accumulation of H + in tumor through the inhibition of mitochondrial complex, which could enhance Fenton catalytic efficiency.…”