Xie Yizhuo, Zhu Ming, Bao Han, Chen Kejia, Wang Shanshan, Dai Jingwen, Chen Hongzhu, Li He, Song Qi, Wang Xinlu, Yu Liangping, Pei Jin
Department of Biopharmacy, School of Pharmaceutical Sciences, Jilin University, Changchun, People's Republic of China.
Department of Clinical Pharmacy, the First Hospital of Jilin University, Changchun, People's Republic of China.
Int J Nanomedicine. 2025 Jan 24;20:1021-1046. doi: 10.2147/IJN.S502076. eCollection 2025.
Colorectal cancer (CRC) is the second leading cause of cancer-related deaths worldwide. Oxaliplatin (OXA) is currently the primary chemotherapeutic agent for CRC, but its efficacy is limited by the tumor microenvironment (TME). Here, we present a combined approach of chemotherapy and TME modulation for CRC treatment. A multifunctional nanosystem (Rg3-Lip-OXA/CaO) was established using Ginsenoside Rg3 liposomes targeting glucose transporter 1 overexpressed on the surface of CRC cells to co-deliver OXA and calcium peroxide (CaO).
The CaO nanoparticles were synthesized via the CaCl-HO reaction under alkaline conditions and characterized using X-ray diffraction (XRD) and X-ray photoelectron spectroscopy (XPS). Rg3-Lip-OXA/CaO was prepared through a thin-film hydration approach and characterized; additionally, its stability and release behavior were studied. The O, HO, and Ca generation ability of Rg3-Lip-OXA/CaO in solution and HCT116 cells were measured. The in vitro cellular uptake was observed via fluorescence microscope and flow cytometry. In vitro cytotoxicity was evaluated using the CCK-8 assay, flow cytometry, and live/dead cell staining. The in vivo targeting effect as well as antitumor efficacy were determined in HCT116 tumor-bearing mice. Finally, the acute toxicity of Rg3-Lip-OXA/CaO was investigated in ICR mice to explore its safety.
The XRD and XPS analyses confirmed the successful synthesis of CaO nanoparticles. The Rg3-Lip-OXA/CaO exhibited an average particle size of approximately 92.98 nm with good stability and sustained release behavior. In vitro and in vivo studies confirmed optimal targeting by Rg3-Lip and demonstrated that the nanosystem effectively produced O, HO and Ca, resulting in significant cytotoxicity. Additionally, in vivo studies revealed substantial tumor growth suppression and reduced tumor-associated fibroblasts (TAFs) and collagen. Acute toxicity studies indicated that Rg3-Lip-OXA/CaO markedly reduced the toxicity of chemotherapeutic drugs.
This multifunctional nanosystem enhances chemotherapy efficacy and reduces toxicity, offering a promising approach for optimizing CRC treatment and potential clinical application.
结直肠癌（CRC）是全球癌症相关死亡的第二大主要原因。奥沙利铂（OXA）是目前CRC的主要化疗药物，但其疗效受到肿瘤微环境（TME）的限制。在此，我们提出一种化疗与TME调节相结合的方法用于CRC治疗。利用靶向CRC细胞表面过表达的葡萄糖转运蛋白1的人参皂苷Rg3脂质体建立了一种多功能纳米系统（Rg3-Lip-OXA/CaO），以共同递送OXA和过氧化钙（CaO）。
通过在碱性条件下的CaCl₂-H₂O₂反应合成CaO纳米颗粒，并使用X射线衍射（XRD）和X射线光电子能谱（XPS）对其进行表征。通过薄膜水化法制备Rg3-Lip-OXA/CaO并进行表征；此外，还研究了其稳定性和释放行为。测定了Rg3-Lip-OXA/CaO在溶液和HCT116细胞中的O₂、H₂O₂和Ca²⁺生成能力。通过荧光显微镜和流式细胞术观察体外细胞摄取情况。使用CCK-8法、流式细胞术和活/死细胞染色评估体外细胞毒性。在荷HCT116肿瘤小鼠中测定体内靶向效果以及抗肿瘤疗效。最后，在ICR小鼠中研究Rg3-Lip-OXA/CaO的急性毒性以探索其安全性。
XRD和XPS分析证实成功合成了CaO纳米颗粒。Rg3-Lip-OXA/CaO的平均粒径约为92.98 nm，具有良好的稳定性和缓释行为。体外和体内研究证实Rg3-Lip具有最佳靶向性，并表明该纳米系统能有效产生O₂、H₂O₂和Ca²⁺，从而导致显著的细胞毒性。此外，体内研究显示肿瘤生长受到显著抑制，肿瘤相关成纤维细胞（TAFs）和胶原蛋白减少。急性毒性研究表明，Rg3-Lip-OXA/CaO显著降低了化疗药物的毒性。
这种多功能纳米系统提高了化疗疗效并降低了毒性，为优化CRC治疗及潜在的临床应用提供了一种有前景的方法。
