Jobdeedamrong Arjaree, Yoo Hye Jin, Jung Hosun, Pechyen Chiravoot, Natphopsuk Sitakan, Thongnuek Peerapat, Jeong Seok, Lee Junghan, Yang Su-Geun
BK21 FOUR Program in Biomedical Science and Engineering, Department of Biomedical Science, Inha University College of Medicine, Incheon 22332, Republic of Korea.
Translational Research Center, Biomedical Research Institute, Inha University Hospital, Inha University College of Medicine, Incheon 22332, Republic of Korea.
Int J Mol Sci. 2025 Aug 18;26(16):7965. doi: 10.3390/ijms26167965.
In recent years, combination chemotherapy with therapeutic nucleic acids has emerged as a promising strategy to enhance the effectiveness of cancer therapy. However, developing an effective co-delivery system to simultaneously transport both chemotherapeutic drugs and nucleic acids remains challenging. Herein, we fabricated cholesterol-conjugated polyion complex nanoparticles (PCNs) for combination delivery of hydrophobic paclitaxel (PTX) and hydrophilic miR-34a. Cholesterol was conjugated to polyethylenimine (PEI) and hyaluronic acid (HA), producing C-PEI and C-HA, respectively. PTX was initially encapsulated within the hydrophobic core formed by the self-assembly of C-HA and C-PEI, yielding polyion complex nanoparticles (PTX@C-HA/C-PEI PCNs). Subsequently, the negatively charged miR-34a was electrostatically complexed with the cationic C-PEI moieties to generate miR-34a/PTX@C-HA/C-PEI PCNs. These PCNs exhibited a nanoscale structure with a uniform size distribution and demonstrated low cytotoxicity in colon cancer cells. Fluorescence microscopy confirmed efficient cytosolic delivery of C-HA/C-PEI PCNs in colon carcinoma cells. Furthermore, combination delivery of PTX and miR-34a using C-HA/C-PEI PCNs exhibited significantly enhanced transfection efficiency and cellular uptake for human colon cancer cells. Notably, PTX/miR-34a@C-HA/C-PEI PCNs effectively downregulated critical oncogenic targets, including , , and , resulting in reduced cancer cell migration and proliferation. These findings indicate that PTX/miR-34a@C-HA/C-PEI PCNs hold significant potential as an innovative combination delivery platform, offering improved therapeutic efficacy for colon cancer therapy.
近年来，治疗性核酸联合化疗已成为提高癌症治疗效果的一种有前景的策略。然而，开发一种有效的共递送系统以同时运输化疗药物和核酸仍然具有挑战性。在此，我们制备了胆固醇共轭聚离子复合纳米颗粒（PCNs），用于疏水性紫杉醇（PTX）和亲水性miR-34a的联合递送。胆固醇分别与聚乙烯亚胺（PEI）和透明质酸（HA）共轭，分别产生C-PEI和C-HA。PTX最初被包裹在由C-HA和C-PEI自组装形成的疏水核心内，产生聚离子复合纳米颗粒（PTX@C-HA/C-PEI PCNs）。随后，带负电荷的miR-34a与阳离子C-PEI部分静电复合，生成miR-34a/PTX@C-HA/C-PEI PCNs。这些PCNs呈现出具有均匀尺寸分布的纳米级结构，并在结肠癌细胞中表现出低细胞毒性。荧光显微镜证实了C-HA/C-PEI PCNs在结肠癌细胞中的有效胞质递送能力。此外，使用C-HA/C-PEI PCNs联合递送PTX和miR-34a对人结肠癌细胞表现出显著提高的转染效率和细胞摄取。值得注意的是，PTX/miR-34a@C-HA/C-PEI PCNs有效地下调了关键致癌靶点，包括 、 和 ，导致癌细胞迁移和增殖减少。这些发现表明，PTX/miR-34a@C-HA/C-PEI PCNs作为一种创新的联合递送平台具有巨大潜力，为结肠癌治疗提供了更高的治疗效果。 （注：原文中关键致癌靶点处有缺失内容）
