GSH‐Activated Porphyrin Sonosensitizer Prodrug for Fluorescence Imaging‐Guided Cancer Sonodynamic Therapy

Abstract

Sonodynamic therapy (SDT), which uses ultrasound to trigger a sonosensitizer to generate reactive oxygen species (ROS), is a promising form of cancer therapy with outstanding tissue penetration depth. However, the sonosensitizer may inevitably spread to surrounding healthy tissue beyond the tumor, resulting in undesired side effects under an ultrasound stimulus. Herein, as glutathione (GSH) is overexpressed in the tumor microenvironment, a GSH‐activatable sonosensitizer prodrug is designed by attaching a quencher to tetraphydroxy porphyrin for tumor therapy. The prodrug exhibits poor fluorescence and low ROS generation capacity under ultrasound irradiation, but it also showed that it can be activated by GSH to simultaneously switch on fluorescence emission and ROS generation capability at the tumor site. Compared with the non‐quenched sonosensitizer, the designed prodrug exhibits significantly higher tumor/healthy organ fluorescence ratios, due to the specific fluorescence and ROS activation by overexpressed GSH in the tumor. Finally, the prodrug exhibits efficient tumor growth inhibition under ultrasound irradiation, further demonstrating its promise as a GSH‐activated sonosensitizer prodrug for highly effective cancer treatment.

Ultrasound-Controlled Prodrug Activation: Emerging Strategies in Polymer Mechanochemistry and Sonodynamic Therapy

“…Triggered activation of sensitizers is another strategy shared by PDT and SDT, as exemplified by recent publications from the groups of Ye 138 and An. 139 Ye elegantly designed a self-assembled glutathione (GSH)-activatable nanosensitizer 1-NPs (Figure 14a), composed of two GSH-reducible amphiphilic probes (1-Zn-PPA and 1-NLG). 138 In GSHabundant tumor microenvironments, 1-NPs activate to release Zn-PPA-SH.…”

“…An's design features a tetrahydroxy porphyrin sonosensitizing unit covalently bonded to a GSH-responsive quencher moiety (Figure 14b). 139 In its inactive form, this sensitizer-prodrug shows limited fluorescence and a low capacity for ROS generation under ultrasound irradiation (30 kHz). However, it can be activated by GSH to release tetrahydroxy porphyrin.…”

“…(a) Structures of 1-Zn-PPA and 1-NLG and their proposed coassembly into 1-NPs for sonophotodynamic immunotherapy . (b) A GSH-activated sonosensitizer prodrug was selectively activated at tumor sites for switch-on SDT activity and fluorescence . Adapted with permission from refs and .…”

An Ultrasound-Activated Nanozyme Sonosensitizer for Photoacoustic Imaging-Guided Breast Cancer Sonodynamic and Starvation Combination Therapy

“…Sonodynamic therapy (SDT) is an interesting strategy for tumor treatment, which possesses a series of advantages, such as being safe, noninvasive, and highly penetrating. − The main therapeutic mechanism of SDT is that sonosensitizers absorb ultrasound (US) energy to produce reactive oxygen species (ROS), causing oxidative stress to cells. − Therefore, the performance of the sonosensitizer greatly influences the therapeutic effect of SDT. − Conventional organic sonosensitizers, such as hematoporphyrin, convert oxygen (O 2 ) into singlet oxygen ( 1 O 2 ). − However, this type of sonosensitizers inevitably suffers from disadvantages, such as poor water solubility and poor stability. , Compared with organic sonosensitizers, inorganic sonosensitizers excel in enhancing the therapeutic effect of SDT due to their unique physical properties, such as stability and operability. , Moreover, some inorganic sonosensitizers not only convert O 2 to 1 O 2 but also break down water to produce hydroxyl radicals (·OH). − For example, gold-based nanoparticles have been reported to exhibit sonodynamic effects by the cavitation effect . Alginate-coated Au nanorods could produce 1 O 2 and ·OH for SDT, and the production and collapse of gas bubbles further enhance the cavitation effect .…”

Defect-rich sonosensitizers based on CeO2 with Schottky heterojunctions for boosting sonodynamic/chemodynamic synergistic therapy

“…1–5 Sonodynamic therapy (SDT) as a promising treatment has attracted intensive attention due to its advantages of non-invasiveness, deep tissue penetration, good specificity, and low side effects. 6–10 Sonosensitizers are one of the keys to determining the efficacy of SDT. The commonly used organic sonosensitizers, for example, protoporphyrin (PpIX) and tetracarboxyphenylporphine (TCPP), often suffer from issues of poor water solubility, low stability, rapid metabolism, and inferior enrichment in tumors.…”