Department of Pharmacy Health and Nutritional Science, University of Calabria, 87036 Rende (CS), Italy.
Int J Mol Sci. 2024 Sep 30;25(19):10560. doi: 10.3390/ijms251910560.
This study introduces novel CD44-targeted and redox-responsive nanoparticles (FNPs), proposed as doxorubicin (DOX) delivery devices for breast cancer. A cationized and redox-responsive Human Serum Albumin derivative was synthesized by conjugating Human Serum Albumin with cystamine moieties and then ionically complexing it with HA. The suitability of FNPs for cancer therapy was assessed through physicochemical measurements of size distribution (mean diameter of 240 nm), shape, and zeta potential (15.4 mV). Nanoparticles possessed high DOX loading efficiency (90%) and were able to trigger the drug release under redox conditions of the tumor environment (55% release after 2 h incubation). The use of the carrier increased the cytotoxic effect of DOX by targeting the CD44 protein. It was shown that, upon loading, the cytotoxic effect of DOX was enhanced in relation to CD44 protein expression in both 2D and 3D models. DOX@FNPs significantly decrease cellular metabolism by reducing both oxygen consumption and extracellular acidification rates. Moreover, they decrease the expression of proteins involved in the oxidative phosphorylation pathway, consequently reducing cellular viability and motility, as well as breast cancer stem cells and spheroid formation, compared to free DOX. This new formulation could become pioneering in reducing chemoresistance phenomena and increasing the specificity of DOX in breast cancer patients.
本研究介绍了一种新型的 CD44 靶向和氧化还原响应性纳米颗粒（FNPs），拟作为乳腺癌的多柔比星（DOX）递送系统。通过将半胱胺与牛血清白蛋白偶联，然后与 HA 离子复合，合成了一种阳离子化和氧化还原响应性的牛血清白蛋白衍生物。通过对粒径分布（平均直径 240nm）、形状和 Zeta 电位（15.4mV）的物理化学测量，评估了 FNPs 用于癌症治疗的适用性。纳米颗粒具有高 DOX 负载效率（90%），并能够在肿瘤环境的氧化还原条件下触发药物释放（孵育 2 小时后释放 55%）。该载体的使用通过靶向 CD44 蛋白增加了 DOX 的细胞毒性作用。结果表明，在负载后，DOX 的细胞毒性作用在 2D 和 3D 模型中均与 CD44 蛋白表达相关增强。与游离 DOX 相比，DOX@FNPs 通过降低耗氧量和细胞外酸化速率，显著降低细胞代谢。此外，它们还降低了参与氧化磷酸化途径的蛋白质的表达，从而降低了细胞活力和迁移能力，以及乳腺癌干细胞和球体形成能力。这种新制剂有望在减少化疗耐药现象和提高 DOX 在乳腺癌患者中的特异性方面发挥先驱作用。
