功能化多壳金纳米粒子载药甲氨蝶呤：一种改善抗肿瘤和抗氧化活性及增强生物相容性的创新纳米治疗策略

Multi-shell gold nanoparticles functionalized with methotrexate: a novel nanotherapeutic approach for improved antitumoral and antioxidant activity and enhanced biocompatibility

DRUG DELIVERY

影响因子:8.1

分区:医学2区 / 药学1区

发表日期:2024 Dec

作者: Denisse-Iulia Bostiog, Natalia Simionescu, Adina Coroaba, Ioana C Marinas, Mariana C Chifiriuc, Gratiela Gradisteanu Pircalabioru, Stelian S Maier, Mariana Pinteala

DOI: 10.1080/10717544.2024.2388624

摘要

甲氨蝶呤（MTX）是一种常用于癌症治疗的叶酸拮抗剂，具有水溶性差和皮肤渗透性低的缺点。这些问题可以通过药物递送系统加以改善，例如功能化的金纳米粒子（AuNPs），其具有多功能性和独特性能。本研究旨在开发以MTX为功能化对象的多壳层AuNPs，以增强MTX的抗肿瘤、抗氧化和生物相容性。合成了稳定的膦配体包覆的AuNPs，并用定制的聚乙二醇（PEG）和短支聚乙烯亚胺（PEI）进行功能化，随后通过共价结合实现MTX固定。采用紫外-可见光谱和傅里叶变换红外光谱（FTIR）、动态光散射（DLS）、扫描透射电子显微镜（STEM）和X射线光电子能谱（XPS）对每一步的产物进行表征。利用DPPH自由基清除、铁离子还原抗氧化能力（FRAP）和铜离子还原抗氧化能力（CUPRAC）等方法测定功能化AuNPs的抗氧化活性。在HaCaT人角化细胞和CAL27鳞状细胞癌细胞系上通过MTT和LDH试验评估其生物相容性和细胞毒性。结果显示，MTX功能化AuNPs具有增强的抗氧化能力，且对肿瘤细胞表现出明显的细胞毒性作用，优于其单一组分，显示出其在癌症治疗中的潜力。

Abstract

Methotrexate (MTX) is a folic acid antagonist routinely used in cancer treatment, characterized by poor water solubility and low skin permeability. These issues could be mitigated by using drug delivery systems, such as functionalized gold nanoparticles (AuNPs), known for their versatility and unique properties. This study aimed to develop multi-shell AuNPs functionalized with MTX for the improvement of MTX antitumoral, antioxidant, and biocompatibility features. Stable phosphine-coated AuNPs were synthesized and functionalized with tailored polyethylene glycol (PEG) and short-branched polyethyleneimine (PEI) moieties, followed by MTX covalent binding. Physicochemical characterization by UV-vis and Fourier-transform infrared spectroscopy (FTIR) spectroscopy, dynamic light scattering (DLS), scanning transmission electron microscopy (STEM), and X-ray photoelectron spectroscopy (XPS) confirmed the synthesis at each step. The antioxidant activity of functionalized AuNPs was determined using DPPH radical scavenging assay, ferric ions' reducing antioxidant power (FRAP), and cupric reducing antioxidant capacity (CUPRAC) assays. Biocompatibility and cytotoxicity were assessed using MTT and LDH assays on HaCaT human keratinocytes and CAL27 squamous cell carcinoma. MTX functionalized AuNPs demonstrated enhanced antioxidant activity and a pronounced cytotoxic effect on the tumoral cells compared to their individual components, highlighting their potential for improving cancer therapy.