Jana Pradip, Sa Pratikshya, Sakai Kentaro, Sahoo Sanjeeb Kumar, Madhyastha Harishkumar, Dev Abhimanyu
Department of Pharmaceutical Sciences & Technology, Birla Institute of Technology, Mesra, Ranchi, Jharkhand 835215, India.
Institute of Life Sciences, Nalco Square, Bhubaneswar 751023, Odisha, India.
Mol Pharm. 2025 Oct 6;22(10):6120-6140. doi: 10.1021/acs.molpharmaceut.5c00823. Epub 2025 Sep 12.
Breast cancer is one of the most common forms of cancer, and an alternate treatment strategy for breast cancer is of utmost importance, as conventional therapy brings severe side effects. Here, we have developed a hyaluronic acid (HA) and cyclic arginine-glycine-aspartic acid peptide (cRGD)-conjugated docetaxel (DTX)-loaded nitrogen-doped carbon dot (CDU)-targeted delivery system for breast cancer. The developed dual-ligand-conjugated system (cRGD-HA-CDU@DTX) has exhibited a size below 100 nm, a high ζ potential (-24.3 mV), good biocompatibility, and good hydrophilicity. The cRGD-HA-CDU@DTX system has demonstrated a high drug loading efficiency (77.53%) and shown an acidic pH (pH 5.0)-dependent drug release of 90% after 48 h. According to the cytotoxicity study in the Michigan Cancer Foundation-7 (MCF-7) cancer cell line, the IC value for the cRGD-HA-CDU@DTX system is found to be 3.167 μM, while for DTX, it is found to be 4.068 μM, indicating better cytotoxicity of the dual-ligand-conjugated system. Cellular uptake study exhibited the excellent internalization of the dual-ligand-conjugated system and a higher reactive oxygen species (ROS) production in cRGD-HA-CDU@DTX as compared to native DTX is seen. Flow cytometry analysis in MCF-7 cells demonstrated an almost 3-fold increased apoptotic cell death for the cRGD-HA-CDU@DTX group compared to DTX alone. Additionally, cell cycle analysis revealed 15% G/M arrest in the cRGD-HA-CDU@DTX-treated cells, whereas only 3.6% G/M arrest was noted for DTX. Further, the cRGD-HA-CDU@DTX system exhibited a significant upregulation and downregulation of proapoptotic and antiapoptotic genes, respectively. Finally, antitumor study displayed a 64.12% tumor growth reduction in the cRGD-HA-CDU@DTX-treated group, while DTX exhibited only a 39.98% tumor growth reduction. Thus, the overall study demonstrated that the cRGD-HA-CDU@DTX system can serve as a potential targeted nanodrug delivery system to reduce side effects and to improve therapeutic efficacy in breast cancer.
乳腺癌是最常见的癌症形式之一，由于传统疗法会带来严重的副作用，因此乳腺癌的替代治疗策略至关重要。在此，我们开发了一种用于乳腺癌的、负载有透明质酸（HA）和环化精氨酸-甘氨酸-天冬氨酸肽（cRGD）偶联多西他赛（DTX）的氮掺杂碳点（CDU）靶向递送系统。所开发的双配体偶联系统（cRGD-HA-CDU@DTX）粒径小于100 nm，ζ电位高（-24.3 mV），具有良好的生物相容性和亲水性。cRGD-HA-CDU@DTX系统表现出较高的载药效率（77.53%），并在48小时后呈现出pH 5.0的酸性环境下90%的药物释放。根据在密歇根癌症基金会-7（MCF-7）癌细胞系中的细胞毒性研究，发现cRGD-HA-CDU@DTX系统的IC值为3.167 μM，而DTX的IC值为4.068 μM，这表明双配体偶联系统具有更好的细胞毒性。细胞摄取研究显示双配体偶联系统具有出色的内化能力，并且与天然DTX相比，cRGD-HA-CDU@DTX中活性氧（ROS）的产生更高。MCF-7细胞的流式细胞术分析表明，与单独使用DTX相比，cRGD-HA-CDU@DTX组的凋亡细胞死亡增加了近3倍。此外，细胞周期分析显示，经cRGD-HA-CDU@DTX处理的细胞中有15%出现G/M期阻滞，而DTX处理的细胞中只有3.6%出现G/M期阻滞。此外，cRGD-HA-CDU@DTX系统分别使促凋亡基因和抗凋亡基因显著上调和下调。最后，抗肿瘤研究显示，cRGD-HA-CDU@DTX处理组的肿瘤生长减少了64.12%，而DTX仅使肿瘤生长减少了39.98%。因此，总体研究表明，cRGD-HA-CDU@DTX系统可作为一种潜在的靶向纳米药物递送系统，以减少副作用并提高乳腺癌的治疗效果。
