用于药物递送和乳腺癌体内治疗的 pH 响应叶酸靶向聚合物包覆金纳米粒子的功能设计。

BACKGROUND: Curcumin has been widely used owing to its various medicinal properties including antitumor effects. However, its clinical application is limited by its instability, poor solubility and low bioavailability. Folic acid (FA)-functionalized nanoformulations may enhance the sustained release of an anticancer drug (curcumin) by tumor-specific targeting to improve therapeutic benefit. This study aims to design a nanoconjugate (NC) comprised of folate-curcumin-loaded gold-polyvinylpyrrolidone nanoparticles (FA-CurAu-PVP NPs) for targeted delivery in breast cancer model systems. METHODS: We developed curcumin-loaded FA-functionalized Au-PVP NCs by layer-by-layer assembly. The folic acid-curcumin Au-PVP NCs (FA-CurAu-PVP NCs) were characterized by ultraviolet-visible spectra, Fourier transform infrared spectroscopy, X-ray powder diffraction and thermogravimetric analysis. In vitro anticancer and antimigratory effects of NCs were examined by performing MTT and wound migration assays. The in vivo antitumor efficacy of NCs was investigated using a preclinical breast cancer orthotopic mouse model. RESULTS: Curcumin (40 µg/mL) was loaded along with conjugation of folate onto Au-PVP NPs to form FA-CurAu-PVP NCs. The size and charge of the NCs were increased gradually through layer-by-layer assembly and showed 80% release of curcumin at acidic pH. The NC did not show aggregation when incubated with human serum and mimicked an intrinsic peroxidase-like property in the presence of 3,3',5,5'-tetramethylbenzidine substrate. The MTT data using these NCs showed efficient anticancer activity at lower doses in estrogen/progesterone receptor (ER/PR)-negative cells compared with ER/PR-positive cells. Furthermore, the NCs did not show cytotoxicity at the investigated concentration in human breast epithelial and mouse fibroblast cell lines. They showed inhibitory effects on cell migration and high antitumor efficacy in in vivo analysis. CONCLUSION: These results suggest that folate-based tumor targeting using CurAu-PVP NCs is a promising approach for tumor-specific therapy of breast cancer without harming normal cells.

背景：姜黄素由于具有多种药用特性，包括抗肿瘤作用，因此被广泛应用。然而，由于其不稳定性、低溶解度和生物利用度低，其临床应用受到限制。叶酸（FA）功能化的纳米制剂可以通过肿瘤特异性靶向来增强抗癌药物（姜黄素）的持续释放，从而提高治疗效果。本研究旨在设计一种由叶酸-姜黄素负载的金-聚乙烯吡咯烷酮纳米粒子（FA-CurAu-PVP NPs）组成的纳米复合物（NC），用于在乳腺癌模型系统中进行靶向递药。

方法：我们通过层层组装法制备了负载姜黄素的 FA 功能化 Au-PVP NC。通过紫外可见光谱、傅里叶变换红外光谱、X 射线粉末衍射和热重分析对叶酸-姜黄素 Au-PVP NC（FA-CurAu-PVP NC）进行了表征。通过 MTT 和划痕迁移实验检测 NC 的体外抗癌和抗迁移作用。使用临床前乳腺癌原位小鼠模型研究 NC 的体内抗肿瘤疗效。

结果：姜黄素（40 µg/mL）与 Au-PVP NPs 上的叶酸偶联，形成负载姜黄素的 FA-CurAu-PVP NC。通过层层组装，NC 的粒径和电荷逐渐增大，在酸性 pH 下可实现 80%的姜黄素释放。NC 与人血清孵育时不会聚集，并在存在 3,3',5,5'-四甲基联苯胺底物时表现出内在过氧化物酶样特性。使用这些 NC 的 MTT 数据显示，在雌激素/孕激素受体（ER/PR）阴性细胞中，与 ER/PR 阳性细胞相比，在较低剂量下具有高效的抗癌活性。此外，在所研究的浓度下，NC 在人乳腺上皮细胞和小鼠成纤维细胞系中没有细胞毒性。它们对细胞迁移具有抑制作用，并在体内分析中具有高抗肿瘤疗效。

结论：这些结果表明，使用 CurAu-PVP NC 进行基于叶酸的肿瘤靶向是一种有前途的乳腺癌特异性治疗方法，不会对正常细胞造成伤害。