Wang Zhengbin, Wang Hui, Yang Linnan, Tan Rui, Guan Wenrui, Chen Sixu, Jiang Guowen, Liu Wanqing, Wang Peng, Huang Xiaowan, Liang Chaozhao, Zhang Yunjiao, Zhang Guilong, Zhang Li
Department of Urology, the First Affiliated Hospital of Anhui Medical University, Anhui Province Key Laboratory of Urological and Andrological Diseases Research and Medical Transformation, Anhui Medical University, Hefei, 230022, China.
Center for Scientific Research of the First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China.
J Nanobiotechnology. 2025 May 30;23(1):399. doi: 10.1186/s12951-025-03489-6.
Despite their unique advantages and vast potential, nanomaterials employed in cancer therapy still encounter challenges such as uneven biodistribution, unintended drug leakage, and especially potential tissue damage caused by off-target toxicity. Bioinert nanomaterials, known for their excellent chemical stability, and minimal biological reactivity, can exert localized tumoricidal effects in response to specific external stimuli. However, the lack of precise control or poor penetration depth largely limits the therapeutic efficacy, necessitating the development of innovative stimuli-responsive therapeutic strategies. This study presents an alternative drug-responsive cancer therapeutic approach based on nickel-iron layered double hydroxide (NiFe-LDH), which exhibited negligible toxicity to both normal cells and cancer cells. By conjugating a platelet-derived growth factor receptor (PDGFR)-β-targeting cyclic peptide, NiFe-LDH achieved high specificity for prostate cancer cells, significantly enhancing tumor targeting and accumulation. Upon administration of deferoxamine mesylate (DFOM), an FDA-approved iron chelator, NiFe-LDH transitioned from a "bioinert" state to a "bioactive" nanotherapeutic through structural disassembly and robust release of nickel ions (Ni²⁺). The released ions disrupted mitochondrial function, upregulated insulin-like growth factor binding protein 3 (IGFBP3), and further inhibited the PI3K/AKT/mTOR signaling pathway, consequently leading to potent and selective induction of apoptosis in prostate cancer cells. Unlike conventional therapies, which often cause varying degrees of toxicity in non-target organs, this stimuli-responsive nanoplatform could minimize off-target effects and systemic toxicity by combining the non-toxic LDH with the clinically used DFOM. Our findings demonstrate that DFOM-responsive NiFe-LDH can effectively inhibit tumor growth in both cultured cells and tumor xenografts, suggesting a rational and clinically translatable platform for precision cancer therapy.
尽管用于癌症治疗的纳米材料具有独特优势和巨大潜力，但仍面临诸如生物分布不均、意外药物泄漏等挑战，尤其是脱靶毒性导致的潜在组织损伤。生物惰性纳米材料以其优异的化学稳定性和最小的生物反应性而闻名，可在特定外部刺激下发挥局部杀瘤作用。然而，缺乏精确控制或穿透深度不佳在很大程度上限制了治疗效果，因此需要开发创新的刺激响应治疗策略。本研究提出了一种基于镍铁层状双氢氧化物（NiFe-LDH）的药物响应性癌症治疗方法，该材料对正常细胞和癌细胞均表现出可忽略不计的毒性。通过偶联靶向血小板衍生生长因子受体（PDGFR）-β的环肽，NiFe-LDH对前列腺癌细胞实现了高特异性，显著增强了肿瘤靶向性和积累。在给予美国食品药品监督管理局（FDA）批准的铁螯合剂甲磺酸去铁胺（DFOM）后，NiFe-LDH通过结构解体和镍离子（Ni²⁺）的大量释放，从“生物惰性”状态转变为“生物活性”纳米治疗剂。释放的离子破坏线粒体功能，上调胰岛素样生长因子结合蛋白3（IGFBP3），并进一步抑制PI3K/AKT/mTOR信号通路，从而导致前列腺癌细胞中有力且选择性的凋亡诱导。与传统疗法不同，传统疗法通常会在非靶器官中引起不同程度的毒性，这种刺激响应性纳米平台通过将无毒的LDH与临床使用的DFOM相结合，可将脱靶效应和全身毒性降至最低。我们的研究结果表明，DFOM响应性NiFe-LDH可有效抑制培养细胞和肿瘤异种移植中的肿瘤生长，为精准癌症治疗提供了一个合理且可临床转化的平台。
