Enhanced Antitumor Efficacy and Reduced Toxicity in Colorectal Cancer Using a Novel Multifunctional Rg3-Targeting Nanosystem Encapsulated with Oxaliplatin and Calcium Peroxide

Purpose: 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/CaO₂) was established using Ginsenoside Rg3 liposomes targeting glucose transporter 1 overexpressed on the surface of CRC cells to co-deliver OXA and calcium peroxide (CaO₂). Methods: The CaO₂ nanoparticles were synthesized via the CaCl₂-H₂O₂ reaction under alkaline conditions and characterized using X-ray diffraction (XRD) and X-ray photoelectron spectroscopy (XPS). Rg3-Lip-OXA/CaO₂ was prepared through a thin-film hydration approach and characterized; additionally, its stability and release behavior were studied. The O₂, H₂O₂, and Ca²⁺ generation ability of Rg3-Lip-OXA/ CaO₂ 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/CaO₂ was investigated in ICR mice to explore its safety. Results: The XRD and XPS analyses confirmed the successful synthesis of CaO₂ nanoparticles. The Rg3-Lip-OXA/CaO₂ 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 O₂, H₂O₂ and Ca²⁺, 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/CaO₂ markedly reduced the toxicity of chemotherapeutic drugs. Conclusion: This multifunctional nanosystem enhances chemotherapy efficacy and reduces toxicity, offering a promising approach for optimizing CRC treatment and potential clinical application.