Department of Respiratory Diseases, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, China.
Ningbo Key Laboratory of Biomedical Imaging Probe Materials and Technology, Laboratory of Advanced Theranostic Materials and Technology, Chinese Academy of Sciences (CAS) Key Laboratory of Magnetic Materials and Devices, Ningbo Institute of Materials Technology and Engineering, Chinese Academy of Sciences, Ningbo 315201, China; Zhejiang International Cooperation Base of Biomedical Materials Technology and Application Zhejiang Engineering Research Center for Biomedical Materials, Ningbo Cixi Institute of Biomedical Engineering, Ningbo 315300, China.
Acta Biomater. 2024 Sep 1;185:381-395. doi: 10.1016/j.actbio.2024.07.033. Epub 2024 Jul 25.
Crizotinib (CRZ), one of anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK-TKIs), has emerged as a frontline treatment for ALK-positive (ALK+) lung adenocarcinoma. However, the overexpression of P-glycoprotein (P-gp, a mitochondrial adenosine triphosphate (ATP)-dependent protein) in lung adenocarcinoma lesions causes multidrug resistance (MDR) and limits the efficacy of CRZ treatment. Herein, a mitochondria-targeting nanosystem, zeolitic imidazolate framework-90@indocyanine green (ZIF-90@ICG), was fabricated to intervene in mitochondria and overcome drug resistance. Due to the zinc ion (Zn) interference of ZIF-90 and the photodynamic therapy (PDT) of ICG, this nanosystem is well suited for damaging mitochondrial functions, thus downregulating the intracellular ATP level and inhibiting P-gp expression. In addition, systematic bioinformatics analysis revealed the upregulation of CD44 in CRZ-resistant cells. Therefore, hyaluronic acid (HA, a critical target ligand of CD44) was further modified on the surface of ZIF-90@ICG for active targeting. Overall, this ZIF-90@ICG nanosystem synergistically increased the intracellular accumulation of CRZ and reversed CRZ resistance to enhance its anticancer effect, which provides guidance for nanomedicine design to accurately target tumours and induce mitochondrial damage and represents a viable regimen for improving the prognosis of patients with ALK-TKIs resistance. STATEMENT OF SIGNIFICANCE: The original aim of our research was to combat multidrug resistance (MDR) in highly aggressive and lethal lymphoma kinase-positive (ALK+) lung adenocarcinoma. For this purpose, a cascade-targeted system was designed to overcome MDR, integrating lung adenocarcinoma-targeted hyaluronic acid (HA), mitochondrion-targeted zeolitic imidazolate framework-90 (ZIF-90), the clinically approved drug crizotinib (CRZ), and the fluorescence imaging agent/photosensitizer indocyanine green (ICG). Moreover, using a "two birds with one stone" strategy, ion interference and oxidative stress induced by ZIF-90 and photodynamic therapy (PDT), respectively, disrupt mitochondrial homeostasis, thus downregulating adenosine triphosphate (ATP) levels, inhibiting MDR-relevant P-glycoprotein (P-gp) expression and suppressing tumour metastasis. Overall, this research represents an attempt to implement the concept of MDR reversal and realize the trade-offs between MDR and therapeutic effectiveness.
克唑替尼（CRZ）是一种间变性淋巴瘤激酶酪氨酸激酶抑制剂（ALK-TKI），已成为治疗 ALK 阳性（ALK+）肺腺癌的一线药物。然而，肺腺癌病变中 P 糖蛋白（P-gp，一种线粒体三磷酸腺苷（ATP）依赖性蛋白）的过度表达导致多药耐药（MDR），限制了 CRZ 治疗的疗效。在此，构建了一种靶向线粒体的纳米系统沸石咪唑酯骨架-90@吲哚菁绿（ZIF-90@ICG），以干预线粒体并克服耐药性。由于 ZIF-90 的锌离子（Zn）干扰和吲哚菁绿的光动力疗法（PDT），该纳米系统非常适合破坏线粒体功能，从而下调细胞内 ATP 水平并抑制 P-gp 表达。此外，系统生物信息学分析显示 CRZ 耐药细胞中 CD44 的上调。因此，进一步在 ZIF-90@ICG 表面修饰透明质酸（HA，CD44 的关键靶标配体）进行主动靶向。总体而言，该 ZIF-90@ICG 纳米系统协同增加了 CRZ 的细胞内积累并逆转了 CRZ 耐药性，增强了其抗癌效果，为准确靶向肿瘤并诱导线粒体损伤的纳米医学设计提供了指导，代表了改善 ALK-TKI 耐药患者预后的可行方案。
我们研究的最初目的是对抗高度侵袭性和致命性的淋巴瘤激酶阳性（ALK+）肺腺癌的多药耐药（MDR）。为此，设计了级联靶向系统来克服 MDR，该系统整合了肺腺癌靶向透明质酸（HA）、线粒体靶向沸石咪唑酯骨架-90（ZIF-90）、临床批准的药物克唑替尼（CRZ）和荧光成像剂/光敏剂吲哚菁绿（ICG）。此外，使用“一石二鸟”策略，ZIF-90 引起的离子干扰和光动力疗法（PDT）分别引起的氧化应激破坏了线粒体稳态，从而下调三磷酸腺苷（ATP）水平，抑制与 MDR 相关的 P 糖蛋白（P-gp）表达并抑制肿瘤转移。总体而言，这项研究代表了实施逆转 MDR 概念并实现 MDR 和治疗效果之间权衡的尝试。
