Heydarian Ronak, Divsalar Adeleh, Kouchesfehani Homa Mohseni, Rasouli Milad
Department of Animal Biology, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran.
Department of Cell and Molecular Sciences, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran.
Int J Pharm. 2025 Feb 25;671:125262. doi: 10.1016/j.ijpharm.2025.125262. Epub 2025 Jan 25.
Colorectal cancer (CRC) remains a significant public health concern, emphasizing the need for innovative therapeutic strategies to improve patient outcomes. This study aimed to develop a highly efficient nanocarrier for targeted drug delivery, enhancing drug efficacy while minimizing concentrations and limiting adverse effects. We synthesized protein-based β-lactoglobulin (βlg) nanoparticles (NPs), loaded with 5-fluorouracil (5-FU) and sodium butyrate (NaB), and further functionalized with folic acid (FA) for specific targeting of folate receptor-positive CRC cells. The βlg-5-FU-NaB-FA nanoplatforms exhibited a well-defined size of 208 nm with a narrow size distribution (PDI ≈ 0.5). Zeta potential measurements showed a value of -11.4 mV, indicating stability and suitability for drug delivery. Scanning electron microscopy (SEM) and atomic force microscopy (AFM) confirmed the nanocarrier's spherical morphology and efficient distribution. Drug release profiles demonstrated that the NPs released more drugs at neutral to alkaline pH levels, attributed to pectin's ionization properties. The efficacy of the prepared βlg-5-FU-NaB-FA nanoplatforms was investigated on HCT116 and Caco2 CRC cells, along with the normal cell line CRL-1831. The βlg-5-FU-NaB-FA nanoplatforms exhibited remarkable cytotoxicity against both HCT116 and Caco2 CRC cells compared to free drugs, highlighting the efficacy of targeted delivery in folate receptor-positive cells. These NPs induce cell apoptosis and cell cycle arrest more effectively than free drugs, demonstrating their potential for targeted cancer therapy. Furthermore, a decrease in the expression of crucial genes involved in the Wnt signaling pathway was observed, which offers a valuable understanding of their underlying mechanism. Collectively, our results suggest that the FA-targeted βlg nanocarriers represent a promising platform for the efficient and targeted delivery of 5-FU and NaB in folate receptor-positive CRC. This novel nanocarrier holds the potential to enhance therapeutic outcomes while minimizing side effects, providing a new avenue for the treatment of CRC.
结直肠癌（CRC）仍然是一个重大的公共卫生问题，这凸显了需要创新治疗策略来改善患者预后。本研究旨在开发一种高效的纳米载体用于靶向药物递送，提高药物疗效，同时使药物浓度最小化并限制不良反应。我们合成了负载5-氟尿嘧啶（5-FU）和丁酸钠（NaB）的基于蛋白质的β-乳球蛋白（βlg）纳米颗粒（NPs），并进一步用叶酸（FA）进行功能化，以特异性靶向叶酸受体阳性的结直肠癌细胞。βlg-5-FU-NaB-FA纳米平台呈现出明确的208 nm大小，且粒径分布狭窄（PDI≈0.5）。zeta电位测量显示值为-11.4 mV，表明其稳定性和适合药物递送。扫描电子显微镜（SEM）和原子力显微镜（AFM）证实了纳米载体的球形形态和有效分布。药物释放曲线表明，由于果胶的电离特性，纳米颗粒在中性至碱性pH水平下释放更多药物。在HCT116和Caco2结直肠癌细胞以及正常细胞系CRL-1831上研究了制备的βlg-5-FU-NaB-FA纳米平台的疗效。与游离药物相比，βlg-5-FU-NaB-FA纳米平台对HCT116和Caco2结直肠癌细胞均表现出显著的细胞毒性，突出了在叶酸受体阳性细胞中靶向递送的疗效。这些纳米颗粒比游离药物更有效地诱导细胞凋亡和细胞周期停滞，证明了它们在靶向癌症治疗中的潜力。此外，观察到参与Wnt信号通路的关键基因表达下降，这为理解其潜在机制提供了有价值的信息。总体而言，我们的结果表明，FA靶向的βlg纳米载体是在叶酸受体阳性的结直肠癌中高效、靶向递送5-FU和NaB的有前景的平台。这种新型纳米载体有潜力提高治疗效果，同时将副作用降至最低，为结直肠癌的治疗提供了新途径。
