A computer-aided, carrier-free drug delivery system with enhanced cytotoxicity and biocompatibility: A universal model for multifunctional lung cancer therapy

IF 5.4 2区医学 Q1 BIOPHYSICS Colloids and Surfaces B: Biointerfaces Pub Date : 2025-02-09 DOI:10.1016/j.colsurfb.2025.114557

Zhonglei Wang , Wenjing Xu , Shizeng Lei , Yuxin Lai , Yingying Zhang , Ying Wang , Ziling Xiang , Xin Fu , Liyan Yang

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引用次数: 0

Abstract

Erlotinib (ERL) is a first-line targeted therapy for patients with epidermal growth factor receptor (EGFR)-mutant advanced non-small cell lung cancer (NSCLC). However, its effectiveness is hindered by acquired resistance and poor bioavailability. Carrier-free nanodrugs are a research hotspot due to their efficient targeting, high drug loading capacity, and the absence of any excipients. Herein, we report an advanced self-delivery system for multimodal NSCLC therapy using a computer-aided strategy. First, we developed a novel heterodimer, ERL-SS-QM (ERL conjugated with QM-OH—a hydrophobic aggregation-induced emission fluorophore—via a disulfide bond [SS]), which serves as both cargo and carrier material. Self-assembly is driven by multiple noncovalent interactions, including π-π stacking and sulfur bonds. Subsequently, an ERL-SS-QM-based "triadic" drug delivery nanoplatform comprising 21 variants was developed. A case study on ursolic acid (UA)-loaded ERL-SS-QM nanoparticles (named UA@ERL-SS-QM NPs) revealed narrow size distribution, small particle size, and well stabilized (zeta potential = −28.9 mV). The UA@ERL-SS-QM NPs demonstrated concentration-dependent toxicity against targeted A549 cells (IC₅₀ = 4.36 μM), outperforming free monomeric drugs ERL (IC₅₀ = 12.94 μM) and UA (IC₅₀ = 12.21 μM), indicating good efficiency. Conversely, these NPs exhibited minimal cytotoxicity in non-targeted BEAS-2B cells, suggesting favorable biocompatibility. Upon endocytosis and interaction with overexpressed GSH in A549 cells, the disulfide-bond linker is cleaved to release three components: ERL, UA (which downregulates β-catenin/TCF4/CT45A2 signaling pathways, inducing apoptosis in ERL-resistant L858R/T790M mutant cells—a key factor in acquired resistance to ERL treatment), and QM-OH. Hence, this work provides a universal model for multifunctional NSCLC therapy that effectively addresses ERL resistance while enhancing cytotoxicity and biocompatibility.

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来源期刊

Colloids and Surfaces B: Biointerfaces 生物-材料科学：生物材料

CiteScore

11.10

自引率

3.40%

发文量

730

审稿时长

42 days

期刊介绍： Colloids and Surfaces B: Biointerfaces is an international journal devoted to fundamental and applied research on colloid and interfacial phenomena in relation to systems of biological origin, having particular relevance to the medical, pharmaceutical, biotechnological, food and cosmetic fields. Submissions that: (1) deal solely with biological phenomena and do not describe the physico-chemical or colloid-chemical background and/or mechanism of the phenomena, and (2) deal solely with colloid/interfacial phenomena and do not have appropriate biological content or relevance, are outside the scope of the journal and will not be considered for publication. The journal publishes regular research papers, reviews, short communications and invited perspective articles, called BioInterface Perspectives. The BioInterface Perspective provide researchers the opportunity to review their own work, as well as provide insight into the work of others that inspired and influenced the author. Regular articles should have a maximum total length of 6,000 words. In addition, a (combined) maximum of 8 normal-sized figures and/or tables is allowed (so for instance 3 tables and 5 figures). For multiple-panel figures each set of two panels equates to one figure. Short communications should not exceed half of the above. It is required to give on the article cover page a short statistical summary of the article listing the total number of words and tables/figures.