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Degradable Nanoregulators Based on Ultra-Small Ferrous Sulfide for Photoacoustic/Magnetic Resonance Imaging-Guided
Jingjing Wang1,2, Rui Zhang3, Shen Gao4
1School of Materials, Shenzhen Campus of Sun Yat-sen University, Shenzhen, 518107, China.
Abstract:
Malignant tumors pose a great threat to human health due to their abnormal vascular system and high interstitial density, leading to high invasiveness and low curability. Tumor vasodilation and ensuring deep drug delivery are essential to elevating tumor elimination efficiency. Herein, a powerful nanoregulator is reported with tumor vessel vasodilation and tumor microenvironment (TME) reconstruction capacity for photoacoustic/magnetic resonance imaging-guided tumor starvation and ferroptosis therapy. This nanoregulator uses ultra-small ferrous sulfide (FeS) nanoparticles as a Fenton agent and hydrogen sulfide (H2S) as a donor. Additionally, glucose oxidase (GOx) serves as a glucose-depleting agent and poly (lactic-co-glycolic) acid (PLGA) functions as a building block. PLGA@ultra-small FeS-GOx nanoregulators can simultaneously promote accumulation and enhance penetration deep into tumors through H2S-induced vasodilation and acid-responsive degradation. Further, the TME can be regulated toward aggravated acidity, hydrogen peroxide up-regulation, glutathione down-regulation, and triphosadenine down-regulation by the released ferrous ion (Fe2+), H2S, and GOx. A large amount of lipid hydroperoxides (LPOs) accumulate in this antioxidant system-disabled microenvironment through the Fe2+-mediated Fenton reaction. In vivo data reveal that this synergistic energy depletion-induced starvation and LPO accumulation-driven ferroptosis efficiently kill tumor cells. This approach can guide the development of nanomedicines with clinical translation potential.
Insights
This study introduces a nanoregulator that improves cancer treatment by dilating tumor blood vessels and reconstructing the tumor microenvironment (TME). This approach enhances drug delivery, leading to effective tumor cell death via starvation and ferroptosis.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Oncology
Background:
- Malignant tumors present challenges in treatment due to abnormal vasculature and dense interstitial spaces, leading to poor drug delivery and low curability.
- Effective tumor elimination requires strategies to improve vasodilation and ensure deep drug penetration into the tumor site.
Purpose of the Study:
- To develop and evaluate a novel nanoregulator capable of tumor vasodilation and tumor microenvironment (TME) reconstruction for enhanced cancer therapy.
- To investigate the potential of this nanoregulator in guiding photoacoustic/magnetic resonance imaging-guided tumor starvation and ferroptosis therapy.
Main Methods:
- Fabrication of poly (lactic-co-glycolic) acid (PLGA) encapsulated ultra-small ferrous sulfide (FeS) nanoparticles and glucose oxidase (GOx) (PLGA@ultra-small FeS-GOx).
- Utilizing FeS as a Fenton agent and hydrogen sulfide (H2S) donor, with GOx as a glucose-depleting agent.
- Assessing nanoregulator accumulation, tumor penetration, TME modulation (acidity, oxidative stress), and therapeutic efficacy in vivo.
Main Results:
- The PLGA@ultra-small FeS-GOx nanoregulators induced H2S-mediated vasodilation and acid-responsive degradation, promoting deep tumor penetration.
- The nanoregulator effectively reconstructed the TME by increasing acidity, hydrogen peroxide, and Fe2+ levels, while decreasing glutathione and ATP.
- This TME modulation led to significant accumulation of lipid hydroperoxides (LPOs) and efficient tumor cell killing through synergistic starvation and ferroptosis.
Conclusions:
- The developed nanoregulator demonstrates significant potential for reconstructing the TME and enhancing cancer therapy through combined starvation and ferroptosis.
- This approach offers a promising strategy for developing nanomedicines with potential for clinical translation in cancer treatment.
