Key Takeaways & Executive Findings
- •• • dIR-CDF achieves covalent tumor targeting via sulfenic acid-specific reaction, enhancing tumor accumulation and retention; in vivo studies demonstrate efficient NSCLC tumor suppression in living mice, underscoring its clinical potential for precise theranostics. • • The probe enables NIR imaging-guided therapy under 808 nm irradiation, combining photodynamic effect (1O2 generation) with ferrocene-mediated ferroptosis (·OH production via Fenton reaction), synergistically amplifying oxidative damage and lipid peroxidation. • • The system specifically targets integrin αvβ3-positive NSCLC cells, leveraging the overexpression of sulfenated proteins in the tumor microenvironment, which significantly improves specificity over conventional untargeted agents. • • The covalent immobilization strategy, based on 1,3-cyclohexanedione-sulfenic acid reaction, ensures prolonged retention at the tumor site, addressing the bottleneck of rapid clearance and low drug accumulation seen in traditional nanomedicines.
Abstract
Lung cancer, particularly non-small cell lung cancer (NSCLC), remains a leading cause of cancer-related mortality, with conventional therapies hampered by poor tumor specificity, low drug accumulation, and suboptimal efficacy. To address these challenges, we rationally designed a tumor-targeted, ferrocene-bearing, covalently immobilizable theranostic probe, dIR-CDF, for near-infrared (NIR) imaging-guided photodynamic-ferroptosis synergistic therapy. The probe exploits the overexpression of sulfenated proteins in the tumor microenvironment to specifically target integrin αvβ3-positive NSCLC cells and undergo covalent anchoring via the reaction between 1,3-cyclohexanedione and sulfenic acid, thereby enhancing tumor accumulation and retention. Under 808 nm irradiation, dIR-CDF generates singlet oxygen (1O2) for photodynamic therapy (PDT), while the sustained release of ferrocene catalyzes Fenton reactions to produce hydroxyl radicals (·OH), inducing ferroptosis. The synergistic action of PDT and ferroptosis amplifies lipid peroxidation and disrupts antioxidant defenses, leading to efficient suppression of NSCLC tumors in living mice. This work presents a universal and powerful theranostic platform for precise cancer diagnosis and treatment, with the covalent targeting strategy offering enhanced specificity and retention.
1. Introduction
Lung cancer remains the leading cause of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) accounting for the majority of cases. Despite advances in diagnostic and therapeutic modalities, conventional approaches suffer from inadequate tumor targeting, low drug accumulation at the tumor site, and suboptimal therapeutic outcomes, particularly in late-stage patients. The high heterogeneity of NSCLC and the lack of early specific symptoms further complicate effective intervention, underscoring the urgent need for precision theranostic systems that can integrate accurate diagnosis and efficient therapy.
Photodynamic therapy (PDT) offers a non-invasive modality that generates cytotoxic singlet oxygen (1O2) upon light activation, yet its efficacy is limited by the hypoxic tumor microenvironment and poor light penetration. Ferroptosis, an iron-dependent form of cell death, provides a complementary strategy by exploiting Fenton chemistry to produce highly reactive hydroxyl radicals (·OH) from endogenous hydrogen peroxide, thereby amplifying oxidative stress. However, the clinical translation of ferroptosis inducers is hindered by their lack of tumor specificity and suboptimal bioavailability. The dIR-CDF probe addresses these bottlenecks by integrating a tumor-targeting moiety (1,3-cyclohexanedione) that covalently binds to sulfenated proteins overexpressed in the tumor microenvironment, ensuring selective accumulation and retention. This covalent anchoring, combined with the synergistic action of PDT and ferroptosis, offers a robust approach to overcome the limitations of existing therapies, providing a universal platform for precise cancer treatment.
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Yurong Fan, Hongyuan Wen, Zhitao Zhu, Chaoxiang Cui, Yuqi Zhang, Zhongsheng Zhao, Miao Li, Yiming Feng, Mei Hu, Xingxiang Ren, Zhengzhong Lv, Zhixin Han, Haibin Shi, Guohua Fan (2026). A covalent tumor-targeted theranostic system for NIR imaging-guided photodynamic-ferroptosis synergistic therapy of lung cancer. SCIENCE CHINA Materials. https://doi.org/10.1007/s40843-025-4008-2
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Frequently Asked Questions
What is the mechanism of covalent tumor targeting in dIR-CDF, and how does it enhance tumor retention compared to non-covalent approaches?
dIR-CDF utilizes a 1,3-cyclohexanedione (CD) moiety that specifically reacts with sulfenic acid groups on proteins overexpressed in the tumor microenvironment. This covalent bond formation anchors the probe within the tumor, significantly prolonging retention time and increasing local drug concentration, as evidenced by enhanced tumor accumulation and suppression in living mice.
How does the combination of photodynamic therapy and ferroptosis overcome the limitations of each modality alone?
PDT generates 1O2 but is limited by hypoxia, while ferroptosis relies on Fenton reaction to produce ·OH from H2O2. The dIR-CDF system releases ferrocene to catalyze ·OH generation, which synergizes with PDT-produced 1O2 to amplify lipid peroxidation and disrupt antioxidant defenses, thereby enhancing cytotoxicity even under hypoxic conditions.
What is the significance of targeting integrin αvβ3 and sulfenated proteins in NSCLC?
Integrin αvβ3 is overexpressed on NSCLC cells and tumor vasculature, facilitating specific binding. Sulfenated proteins are elevated in the tumor microenvironment, enabling covalent anchoring. This dual targeting ensures high specificity and retention, reducing off-target effects and improving therapeutic index.
What are the potential scalability and translational challenges for dIR-CDF from preclinical studies to clinical application?
Key challenges include ensuring biocompatibility and long-term safety of the ferrocene component, optimizing the synthesis for large-scale production, and validating efficacy in human clinical trials. The covalent targeting strategy may also require careful evaluation of potential immunogenicity and off-target covalent modifications.
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