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Metal-Organic Framework Derived Multicomponent Nanoagent as a Reactive Oxygen Species Amplifier for Enhanced
Dongdong Wang1, Huihui Wu2, Guangbao Yang1
1Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, 21 Nanyang Link, Singapore 637371, Singapore.
Abstract:
Intracellular antioxidants such as glutathione (GSH) play a critical role in protecting malignant tumor cells from apoptosis induced by reactive oxygen species (ROS) and in mechanisms of multidrug and radiation resistance. Herein, we rationally design two multicomponent self-assembled photodynamic therapy (PDT) nanoagents, that is, Glup-MFi-c and Glud-MFo-c, which consist of respective GSH-passivation and GSH-depletion linkers in metal-organic frameworks encapsulated with photosensitizers for a deeply comprehensive understanding of GSH-based tumor PDT. Multicomponent coordination, π-π stacking, and electrostatic interactions among metal ions, photosensitizers, and bridging linkers under the protection of a biocompatible polymer generate homogeneous nanoparticles with satisfied size, good colloid stability, and ultrahigh loading capacity. Compared to the GSH-passivated Glup-MFi-c, the GSH-depleted Glud-MFo-c shows pH-responsive release of photosensitizer and [FeIII(CN)6] linker in tumor cells to efficiently deplete intracellular GSH, thus amplifying the cell-killing efficiency of ROS and suppressing the tumor growth in vivo. This study demonstrates that Glud-MFo-c acts as a ROS amplifier, providing a useful strategy to deeply understand the role of GSH in combating cancer.
Insights
Researchers developed novel nanoparticles for photodynamic therapy (PDT) that deplete glutathione (GSH) in tumor cells. This strategy enhances the cancer-killing effects of reactive oxygen species (ROS), offering a new approach to combat cancer.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Oncology
Background:
- Intracellular glutathione (GSH) protects cancer cells from reactive oxygen species (ROS)-induced apoptosis.
- GSH is implicated in multidrug and radiation resistance in malignant tumors.
- Targeting GSH is a potential strategy to enhance cancer therapy efficacy.
Purpose of the Study:
- To design and synthesize novel multicomponent self-assembled photodynamic therapy (PDT) nanoagents.
- To investigate the role of GSH-depletion versus GSH-passivation in tumor PDT.
- To understand the mechanism of GSH-based tumor PDT for improved cancer treatment.
Main Methods:
- Rational design of two multicomponent self-assembled nanoagents (Glup-MFi-c and Glud-MFo-c) using metal-organic frameworks (MOFs).
- Encapsulation of photosensitizers within MOFs with GSH-passivation or GSH-depletion linkers.
- Evaluation of nanoparticle characteristics (size, stability, loading capacity) and *in vitro* / *in vivo* anti-cancer efficacy.
Main Results:
- Homogeneous nanoparticles with desired properties were generated through multicomponent coordination, π-π stacking, and electrostatic interactions.
- The GSH-depleted nanoagent (Glud-MFo-c) demonstrated pH-responsive release of photosensitizer and linker in tumor cells.
- Glud-MFo-c efficiently depleted intracellular GSH, amplified ROS-induced cell killing, and suppressed tumor growth *in vivo* compared to Glup-MFi-c.
Conclusions:
- Glud-MFo-c acts as a potent ROS amplifier by depleting intracellular GSH.
- This study provides a valuable strategy to elucidate the role of GSH in cancer therapy.
- The developed nanoagents offer a promising approach for enhancing tumor PDT efficacy.
