Tseriotis Vasilis-Spyridon, Ampazis Dimitrios, Karachrysafi Sofia, Papamitsou Theodora, Petrakis Georgios, Kouvelas Dimitrios, Mavropoulos Paraskevas, Lallas Konstantinos, Sič Aleksandar, Fouskas Vasileios, Stergiou Konstantinos, Pavlidis Pavlos, Arnaoutoglou Marianthi
Department of Neurology, Agios Pavlos General Hospital of Thessaloniki, Leoforos Ethnikis Antistaseos 161, Kalamaria, 55134 Thessaloniki, Greece.
Laboratory of Clinical Pharmacology, Aristotle University Campus, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece.
Int J Mol Sci. 2025 Aug 29;26(17):8417. doi: 10.3390/ijms26178417.
Cancer, a leading global cause of death responsible for nearly 10 million deaths annually, demands innovative therapeutic strategies. Intrinsic cytotoxicity and biocompatibility of zinc oxide nanoparticles (ZnO-NPs) have rendered them promising nanoplatforms in oncology. We herein systematically review their applications for targeted cancer chemotherapy, with a focus on physicochemical properties, drug delivery mechanisms, and interactions with the tumor microenvironment (TME). We searched PubMed, SCOPUS, and Web of Science from inception through December 2024 for peer-reviewed preclinical studies on cancer models. Results were qualitatively synthesized. Quality was assessed with the SYRCLE risk of bias tool. Among 20 eligible studies, ZnO-NPs were frequently functionalized with ligands to enhance tumor targeting and minimize systemic toxicity. Chemotherapeutic agents (doxorubicin, 5-fluorouracil, docetaxel, cisplatin, gemcitabine, and tirapazamine) were loaded into ZnO-based carriers, with improved anticancer efficacy compared to free drug formulations, particularly in multidrug-resistant cell lines and in vivo murine xenografts. The mildly acidic TME was exploited for pH-responsive drug release, premature leakage reduction, and improvement of intratumoral accumulation. Enhanced therapeutic outcomes were attributed to reactive oxygen species generation, zinc ion-mediated cytotoxicity, mitochondrial dysfunction, and efflux pump inhibition. Deep tumor penetration, apoptosis induction, and tumor growth suppression were also reported, with minimal toxicity to healthy tissues. ZnO-NPs might constitute a versatile and promising strategy for targeted cancer chemotherapy, offering synergistic anticancer effects and improved safety profiles. Future studies emphasizing long-term toxicity, immune responses, and scalable production could lead to clinical translation of ZnO-based nanomedicine in oncology.
癌症是全球主要的死亡原因之一，每年导致近1000万人死亡，因此需要创新的治疗策略。氧化锌纳米颗粒（ZnO-NPs）的内在细胞毒性和生物相容性使其成为肿瘤学中很有前景的纳米平台。我们在此系统地综述了它们在靶向癌症化疗中的应用，重点关注其物理化学性质、药物递送机制以及与肿瘤微环境（TME）的相互作用。我们检索了PubMed、SCOPUS和Web of Science从创刊到2024年12月的关于癌症模型的同行评审临床前研究。对结果进行了定性综合。使用SYRCLE偏倚风险工具评估质量。在20项符合条件的研究中，ZnO-NPs经常用配体进行功能化，以增强肿瘤靶向性并最小化全身毒性。将化疗药物（阿霉素、5-氟尿嘧啶、多西他赛、顺铂、吉西他滨和替拉帕米）负载到基于ZnO的载体中，与游离药物制剂相比，抗癌疗效有所提高，特别是在多药耐药细胞系和体内小鼠异种移植模型中。利用轻度酸性的TME进行pH响应性药物释放、减少过早泄漏并改善肿瘤内蓄积。增强的治疗效果归因于活性氧的产生、锌离子介导的细胞毒性、线粒体功能障碍和外排泵抑制。还报道了其对肿瘤的深度渗透、诱导凋亡和抑制肿瘤生长，对健康组织的毒性最小。ZnO-NPs可能构成一种通用且有前景的靶向癌症化疗策略，具有协同抗癌作用并改善安全性。未来强调长期毒性、免疫反应和可扩展生产的研究可能会使基于ZnO的纳米药物在肿瘤学中实现临床转化。
