Wang Liyin, Ashrafizadeh Milad, Sethi Gautam, Zhou Xinjia
Department of Otolaryngology Head and Neck Surgery, Shengjing Hospital of China Medical University, Shenyang, 110004, China.
Department of Radiation Oncology, Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences, Jinan, 250000, China.
J Pharm Anal. 2025 Jul;15(7):101203. doi: 10.1016/j.jpha.2025.101203. Epub 2025 Jan 23.
Suboptimal treatment of laryngeal squamous cell carcinoma (LSCC) provides poor survival rate. The poor bioavailability, resistance to cetuximab (Cet), and the instability of small interfering RNA (siRNA) limit their efficacy in LSCC therapy. The present study has been aimed to develop a Cet and focal adhesion kinase (FAK) siRNA (siFAK) co-delivery nanosystem. Zeolitic imidazolate framework-8 (ZIF-8), with its large specific surface area and pH-responsive properties, is an ideal delivery carrier allowing controlled drug release in the acidic tumor microenvironment. Therefore, Cet was loaded onto ZIF-8 and encapsulated in a TU177 cell membrane (TCM) after the electrostatic adsorption of siFAK. Fourier transform infrared (FTIR) spectroscopy, transmission electron microscopy (TEM), scanning electron microscopy (SEM), zeta potential, X-ray diffraction, and particle size analyses were deployed to characterize Cet/siFAK@ZIF-8@TCM. TU177 cells and subcutaneously transplanted tumor-bearing nude mice were used to evaluate the intracellular uptake, cytotoxicity, biocompatibility, biodistribution, biosafety, pH responsiveness, and anti-LSCC efficacy of Cet/siFAK@ZIF-8@TCM. After ZIF-8@TCM were loaded with Cet and siFAK, alterations in their physical and crystal structures, particle size, and zeta potential were observed. Meanwhile, the co-delivery system increased the loading of Cet through the electrostatic adsorption of siFAK to Cet-loaded ZIF-8. The intracellular uptake of Cet/siFAK@ZIF-8@TCM also protected siFAK from degradation, effectively decreasing the messenger RNA (mRNA) and protein expression levels of FAK in LSCC cells. The ZIF-8@TCM nanosystem for co-delivery of Cet and siFAK exhibited pH-responsiveness and tumor-targeting capabilities, thereby exerting anti-LSCC effects. Co-delivery of Cet and siFAK via the pH-responsive ZIF-8@TCM system enabled the targeted release of the chemotherapeutic and gene, in turn maximizing their anti-LSCC effect while ensuring biosafety.
喉鳞状细胞癌（LSCC）治疗不充分会导致生存率低下。生物利用度差、对西妥昔单抗（Cet）耐药以及小干扰RNA（siRNA）的不稳定性限制了它们在LSCC治疗中的疗效。本研究旨在开发一种Cet与粘着斑激酶（FAK）siRNA（siFAK）共递送纳米系统。沸石咪唑酯骨架-8（ZIF-8）具有大比表面积和pH响应特性，是一种理想的递送载体，可在酸性肿瘤微环境中实现药物的可控释放。因此，在siFAK静电吸附后，将Cet负载到ZIF-8上并封装在TU177细胞膜（TCM）中。采用傅里叶变换红外（FTIR）光谱、透射电子显微镜（TEM）、扫描电子显微镜（SEM）、zeta电位、X射线衍射和粒径分析对Cet/siFAK@ZIF-8@TCM进行表征。使用TU177细胞和皮下移植荷瘤裸鼠来评估Cet/siFAK@ZIF-8@TCM的细胞内摄取、细胞毒性、生物相容性、生物分布、生物安全性、pH响应性和抗LSCC疗效。在ZIF-8@TCM负载Cet和siFAK后，观察到它们的物理和晶体结构、粒径及zeta电位发生了变化。同时，共递送系统通过siFAK与负载Cet的ZIF-8的静电吸附增加了Cet的负载量。Cet/siFAK@ZIF-8@TCM的细胞内摄取还保护了siFAK不被降解，有效降低了LSCC细胞中FAK的信使核糖核酸（mRNA）和蛋白质表达水平。用于Cet和siFAK共递送的ZIF-8@TCM纳米系统表现出pH响应性和肿瘤靶向能力，从而发挥抗LSCC作用。通过pH响应性ZIF-8@TCM系统共递送Cet和siFAK能够实现化疗药物和基因的靶向释放，进而在确保生物安全性的同时最大化它们的抗LSCC效果。
