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Arsenic Prodrug-Mediated Tumor Microenvironment Modulation Platform for Synergetic Glioblastoma Therapy
Jiliang Yan1,2, Sumaira Hanif1,2, Dongya Zhang1,2
1Henan-Macquarie University Joint Centre for Biomedical Innovation, School of Life Sciences, Henan University, Kaifeng, Henan 475004, China.
Abstract:
Glioblastoma (GBM) has a distinct internal environment characterized by high levels of glutathione (GSH) and low oxygen partial pressure, which significantly restrict most drugs' effectiveness. Arsenic-based drugs are emerging candidates for treating solid tumors; however, relatively high doses in solo systems and inconsistent complementary systems severely damage the normal tissues. We proposed a novel covalently conjugated strategy for arsenic-based therapy via arsenic-boronic acid complex formation. The boronic acid was modified on silver (AgL) to capture AsV under an alkaline condition named arsenate plasmonic complex (APC) with a distinct Raman response. The APC can precisely release the captured AsV in lysosomal acidic pH that specifically targets TME to initiate a multimodal therapeutic effect such as GSH depletion and reactive oxygen species generation. In addition, GSH activation leads to subconverted AsV into AsIII, which further facilitated glutathione peroxidase (GPx) and superoxide dismutase inhibition, whereas the tumor selective etching of the silver core triggered by endogenous H2O2 that can oxidize to generate highly toxic Ag ions produces and supplies O2 to help the alleviated hypoxia. Both in vitro and in vivo data verify the APC-based chemotherapy paving the way for efficient nanomedicine-enabled boronate affinity-based arsenic chemotherapeutics for on demand site-specific cancer combination treatment of GBM tumors.
Insights
This study introduces a novel arsenic-based therapy for glioblastoma (GBM) using an arsenate plasmonic complex (APC). The APC targets the tumor microenvironment, depleting glutathione and generating oxygen to combat hypoxia and enhance chemotherapy effectiveness.
Area of Science:
- Nanomedicine
- Cancer Therapy
- Materials Science
Background:
- Glioblastoma (GBM) presents a challenging tumor microenvironment (TME) with high glutathione (GSH) and hypoxia, limiting drug efficacy.
- Arsenic-based drugs show promise for solid tumors but require careful dosing to avoid normal tissue damage.
- Existing therapies struggle with the unique TME of GBM, necessitating innovative treatment strategies.
Purpose of the Study:
- To develop a novel, site-specific arsenic-based therapeutic strategy for glioblastoma (GBM).
- To engineer an arsenate plasmonic complex (APC) for targeted drug delivery and multimodal tumor treatment.
- To overcome the limitations of the GBM TME and enhance chemotherapeutic outcomes.
Main Methods:
- Conjugation of boronic acid to silver nanoparticles (AgL) to form arsenate plasmonic complexes (APC) capable of capturing AsV.
- Utilizing the acidic lysosomal pH for controlled release of AsV within the tumor microenvironment.
- Investigating the multimodal therapeutic effects including GSH depletion, reactive oxygen species (ROS) generation, enzyme inhibition, and oxygen production.
Main Results:
- The APC effectively releases AsV in the acidic TME, initiating GSH depletion and ROS generation.
- GSH activation leads to AsV to AsIII conversion, inhibiting glutathione peroxidase (GPx) and superoxide dismutase.
- Tumor-selective silver core etching by H2O2 generates toxic Ag+ ions and produces O2, alleviating hypoxia.
Conclusions:
- The developed APC demonstrates efficient, site-specific combination therapy for GBM.
- This nanomedicine-enabled approach offers a promising strategy for overcoming GBM TME challenges.
- Boronate affinity-based arsenic chemotherapeutics represent a novel avenue for on-demand cancer treatment.
