Tumor Microenvironment-Responsive Intelligent Hydrogel Co-Delivery System Enhances Ferroptosis for Triple-Negative Breast Cancer Therapy.

IF 4.1 3区医学 Q2 CHEMISTRY, MULTIDISCIPLINARY

Pharmaceutical Research Pub Date : 2026-09-17 DOI:10.1007/s11095-026-04189-y

Yong Chen, Mingxin Xu, An Liu

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Abstract

Purpose: Triple-negative breast cancer (TNBC) lacks effective therapeutic targets. Aurisin A (AA), a natural sesterterpenoid, shows anti-TNBC potential but is limited by poor water solubility. This study aimed to develop a tumor microenvironment (TME)-responsive co-delivery hydrogel to enhance AA efficacy.

Methods: AA was complexed with hydroxypropyl-β-cyclodextrin (HP-β-CD) to form AA@HP-β-CD, which was co-loaded with acetazolamide (ACZ) into a triple-responsive injectable hydrogel (PCG). The anti-TNBC mechanism was investigated using HCC1937 cells, focusing on ferroptosis induction. In vivo antitumor efficacy and safety were evaluated in a xenograft nude mouse model.

Results: AA@HP-β-CD significantly improved AA solubility and stability. Mechanistically, AA induced ferroptosis in TNBC cells by upregulating HSP90 and promoting GPX4 degradation, leading to glutathione depletion, iron accumulation, and lipid peroxidation. ACZ disrupted intracellular pH homeostasis, further sensitizing cells to AA-induced ferroptosis. The PCG hydrogel enabled sustained, TME-triggered drug release. In the xenograft model, intratumoral injection of PCG/ACZ/AA@HP-β-CD achieved a 76.3% tumor inhibition rate with no observable toxicity to major organs.

Conclusions: The TME-responsive PCG/ACZ/AA@HP-β-CD hydrogel integrates drug solubilization, intelligent delivery, and dual-mechanism enhancement. The combination of AA-induced ferroptosis via the HSP90/GPX4 axis and ACZ-mediated pH disruption represents a promising strategy for TNBC therapy with good biosafety.

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肿瘤微环境响应智能水凝胶共递送系统增强三阴性乳腺癌治疗中的铁下垂。

目的：三阴性乳腺癌缺乏有效的治疗靶点。Aurisin A （AA）是一种天然的酯萜类化合物，具有抗tnbc的潜力，但受水溶性差的限制。本研究旨在开发一种肿瘤微环境（tumor microenvironment， TME）反应性的共给药水凝胶，以提高AA的疗效。方法：AA与羟丙基-β-环糊精（HP-β-CD）络合形成AA@HP-β-CD，与乙酰唑胺（ACZ）共载制成三反应性注射水凝胶（PCG）。采用HCC1937细胞研究其抗tnbc机制，重点关注铁下垂诱导。在异种移植裸鼠模型中评估了体内抗肿瘤疗效和安全性。结果：AA@HP-β-CD显著提高了AA的溶解度和稳定性。机制上，AA通过上调HSP90和促进GPX4降解诱导TNBC细胞铁凋亡，导致谷胱甘肽耗竭、铁积累和脂质过氧化。ACZ破坏细胞内pH稳态，进一步使细胞对aa诱导的铁下垂敏感。PCG水凝胶使tme触发的药物持续释放。在异种移植模型中，瘤内注射PCG/ACZ/AA@HP-β-CD的肿瘤抑制率为76.3%，对主要器官无明显毒性。结论：tme响应型PCG/ACZ/AA@HP-β-CD水凝胶集药物增溶、智能给药和双机制增强于一体。aa通过HSP90/GPX4轴诱导铁凋亡和acz介导的pH破坏相结合，代表了一种有前景的TNBC治疗策略，具有良好的生物安全性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Pharmaceutical Research 医学-化学综合

CiteScore

6.60

自引率

5.40%

发文量

276

审稿时长

3.4 months

期刊介绍： Pharmaceutical Research, an official journal of the American Association of Pharmaceutical Scientists, is committed to publishing novel research that is mechanism-based, hypothesis-driven and addresses significant issues in drug discovery, development and regulation. Current areas of interest include, but are not limited to: -(pre)formulation engineering and processing- computational biopharmaceutics- drug delivery and targeting- molecular biopharmaceutics and drug disposition (including cellular and molecular pharmacology)- pharmacokinetics, pharmacodynamics and pharmacogenetics. Research may involve nonclinical and clinical studies, and utilize both in vitro and in vivo approaches. Studies on small drug molecules, pharmaceutical solid materials (including biomaterials, polymers and nanoparticles) biotechnology products (including genes, peptides, proteins and vaccines), and genetically engineered cells are welcome.