Introduction Lung cancer has a poor prognosis with traditional treatments. Realgar (AS4S4), a traditional Chinese medicine, exhibits chemotherapeutic efficacy. However, its low solubility, complex dosage form, and limited therapeutic efficacy hinder its further application in lung cancer. Methods In this study, AS4S4 was chemically synthesized using hydrochloric acid to disrupt the bonding between AS and NH2, producing realgar nanoclusters that improved solubility and reduced side effects. Simultaneously, Fe3O4 nanoparticles were introduced, and intelligent temperature-sensitive hydrogels were utilized to combine these two performance nanomaterials, developing a local injection nano-diagnosis and treatment unit (AS4S4/Fe3O4@Gel) that integrates chemotherapy with alternating current magnetic field (ACMF) induction hyperthermia. The morphological characteristics, thermal stability, and controlled release of AS4S4/Fe3O4@Gel were assessed. After processing the Lewis cells, the CCK-8 method, hemolysis test, EdU method, cell apoptosis test, reactive oxygen species detection, and cellular ultrastructure analysis were used to evaluate the biological effects. Western blot was employed to detect Bcl-2, BAX, GPX4, and HO-1 protein expression in cells. After injecting the gel system into the transplanted tumor, in vivo imaging, near-infrared thermography, and the antitumor effect were studied. Results AS4S4/Fe3O4@Gel, which exhibits fluorescence and magnetic inductive hyperthermia, was successfully developed. The gel system, which has good hemocompatibility, possesses ideal temperature sensitivity. It can transform from liquid to solid within a specific temperature range, and the drug release rate about 80% within 3 h at 42 °C. Cell experiments showed that the combination of AS4S4/Fe3O4@Gel and ACMF induced the highest levels of apoptosis and ferroptosis. AS4S4/Fe3O4@Gel in vivo displayed good fluorescence characteristics and a magnetocaloric effect. The combination therapy group significantly decreased the expression levels of Ki-67, CD31, E-cadherin, Bcl-2, and GPX4 proteins, indicating that combination therapy can better exert antitumor effects. At the same time, AS4S4/Fe3O4@Gel had no damage to normal organs. Conclusion The prepared AS4S4/Fe3O4@Gel in this study can exert synergistic antitumor activity in combination with ACMF under bimodal imaging guidance and represents a potential clinical treatment for lung cancer.

Integration of temperature-sensitive hydrogels loaded with realgar and magnetic particles for lung cancer diagnosis and treatment

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2025年2月25日

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Tao Jiang,
Zhifei Huang,
Mingdong Reng,
Yuwei Ma,
Bo Gao,
Shilong Song,
Fei Liu,
Xiangyu Zhang,
Jingwen Huang,
Zelai He,
Huijun Zhang,
Jing Ma,
Gengming Wang

摘要

Introduction

Lung cancer has a poor prognosis with traditional treatments. Realgar (AS₄S₄), a traditional Chinese medicine, exhibits chemotherapeutic efficacy. However, its low solubility, complex dosage form, and limited therapeutic efficacy hinder its further application in lung cancer.

Methods

In this study, AS₄S₄ was chemically synthesized using hydrochloric acid to disrupt the bonding between AS and NH₂, producing realgar nanoclusters that improved solubility and reduced side effects. Simultaneously, Fe₃O₄ nanoparticles were introduced, and intelligent temperature-sensitive hydrogels were utilized to combine these two performance nanomaterials, developing a local injection nano-diagnosis and treatment unit (AS₄S₄/Fe₃O₄@Gel) that integrates chemotherapy with alternating current magnetic field (ACMF) induction hyperthermia. The morphological characteristics, thermal stability, and controlled release of AS₄S₄/Fe₃O₄@Gel were assessed. After processing the Lewis cells, the CCK-8 method, hemolysis test, EdU method, cell apoptosis test, reactive oxygen species detection, and cellular ultrastructure analysis were used to evaluate the biological effects. Western blot was employed to detect Bcl-2, BAX, GPX4, and HO-1 protein expression in cells. After injecting the gel system into the transplanted tumor, in vivo imaging, near-infrared thermography, and the antitumor effect were studied.

Results

AS₄S₄/Fe₃O₄@Gel, which exhibits fluorescence and magnetic inductive hyperthermia, was successfully developed. The gel system, which has good hemocompatibility, possesses ideal temperature sensitivity. It can transform from liquid to solid within a specific temperature range, and the drug release rate about 80% within 3 h at 42 °C. Cell experiments showed that the combination of AS₄S₄/Fe₃O₄@Gel and ACMF induced the highest levels of apoptosis and ferroptosis. AS₄S₄/Fe₃O₄@Gel in vivo displayed good fluorescence characteristics and a magnetocaloric effect. The combination therapy group significantly decreased the expression levels of Ki-67, CD31, E-cadherin, Bcl-2, and GPX4 proteins, indicating that combination therapy can better exert antitumor effects. At the same time, AS₄S₄/Fe₃O₄@Gel had no damage to normal organs.

Conclusion

The prepared AS₄S₄/Fe₃O₄@Gel in this study can exert synergistic antitumor activity in combination with ACMF under bimodal imaging guidance and represents a potential clinical treatment for lung cancer.