Purpose: Folic acid and cyclic arginylglycylaspartic acid peptides were introduced to the surface of negatively charged lipid-coated hybrid polydopamine-cysteine cores for the delivery of epirubicin (EPI) (E/PCF-NPs). The combined chemo-photothermal therapy using E/PCF-NPs for triple-negative breast cancer was evaluated.
Materials and Methods: The temperature elevation and thermal toxicity of nanoparticles were studied. The morphology and properties of E/PCF-NPs were characterized by transmission electron microscopy, scanning electron microscopy, and atomic force microscopy. Physicochemical properties, including particle size, zeta potential, drug loading, entrapment efficiency (EE%), stability and in vitro release, were determined. The cell viability, reactive oxygen species (ROS) levels, ratios of oxidized nicotinamide adenine dinucleotide to its reduced form (NAD⁺/NADH), apoptosis assays, and cellular uptake of E/PCF-NPs were determined on 4T1 cells. Pharmacokinetic studies and tissue distributions were performed and detected by an ultra-high performance liquid chromatography/mass spectrometry system. The antitumor effects of E/PCF-NPs under near-infrared (NIR) laser irradiation were also evaluated.
Results: The sphere-like morphology of E/PCF-NPs showed a high EE%, uniform size of 106.7 nm, remarkable stability, and highly improved cytotoxicity under NIR laser, when compared to that of photothermal treatment alone. In vitro release of EPI from E/PCF-NPs was pH sensitive, and a greater response was achieved under NIR laser irradiation. Compared to chemotherapy or photothermal treatment alone, the combined treatment in vitro significantly inhibited the survival rate of 4T1 cells to 17.7%, induced ROS generation, and reduced NAD⁺/NADH significantly. Treatment with E/PCF-NPs under irradiation induced 4T1 cell apoptosis in approximately 93.6% cells. In vitro cellular uptake of E/PCF-NPs was time-dependent. The long-circulating and higher tumor accumulation of E/PCF-NPs resulted in complete ablation of breast tumor tissue through the enhanced photothermal effect by NIR laser irradiation-mediated cell apoptosis.
Conclusion: E/PCF-NPs show enhanced anti-cancer effects due to synergistic effects of chemotherapy with photothermal therapy and may be potential therapeutic agents for cancer treatment.

Keywords: polydopamine nanoparticles, L-cysteine, epirubicin, pharmacokinetics, triple-negative breast cancer


中文翻译：

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自组装双靶向表阿霉素-杂化聚多巴胺纳米颗粒用于三阴性乳腺癌的化疗光热联合治疗


目的：将叶酸和环状精氨酰甘氨酰天冬氨酸肽引入带负电荷的脂质包被杂化聚多巴胺-半胱氨酸核心的表面，用于递送表柔比星 (EPI) (E/PCF-NP)。使用 E/PCF-NPs 联合化疗光热疗法治疗三阴性乳腺癌进行了评估。

材料和方法：研究了纳米粒子的温度升高和热毒性。通过透射电子显微镜、扫描电子显微镜和原子力显微镜对 E/PCF-NP 的形貌和性质进行了表征。测定了物理化学性质，包括粒径、zeta 电位、载药量、包封率 (EE%)、稳定性和体外释放。在 4T1 细胞上测定细胞活力、活性氧 (ROS) 水平、氧化烟酰胺腺嘌呤二核苷酸与其还原形式 (NAD ⁺ /NADH) 的比率、细胞凋亡测定和 E/PCF-NP 的细胞摄取。通过超高效液相色谱/质谱系统进行和检测药代动力学研究和组织分布。还评估了 E/PCF-NP 在近红外 (NIR) 激光照射下的抗肿瘤作用。

结果：与单独光热处理相比，E/PCF-NPs 的球形形态表现出较高的 EE%、106.7 nm 的均匀尺寸、显着的稳定性和在近红外激光下显着改善的细胞毒性。 E/PCF-NPs 的 EPI 体外释放对 pH 敏感，并且在近红外激光照射下实现了更大的响应。与单独化疗或光热治疗相比，体外联合治疗显着抑制4T1细胞的存活率至17.7%，诱导ROS生成，并显着降低NAD ⁺ /NADH。在辐射下用 E/PCF-NP 处理可诱导约 93.6% 的细胞发生 4T1 细胞凋亡。 E/PCF-NP 的体外细胞摄取具有时间依赖性。 E/PCF-NPs的长循环和较高的肿瘤积累通过近红外激光照射介导的细胞凋亡增强的光热效应导致乳腺肿瘤组织完全消融。

结论：由于化疗与光热疗法的协同作用，E/PCF-NPs 表现出增强的抗癌作用，可能成为癌症治疗的潜在治疗剂。


关键词:聚多巴胺纳米粒, L-半胱氨酸, 表柔比星, 药代动力学, 三阴性乳腺癌