Introduction: Oxaliplatin is a third-generation platinum-based chemotherapeutic agent widely used for colorectal cancer treatment. However, its therapeutic application is lim-ited by low solubility, systemic toxicity, and poor bioavailability. Methods: Solid lipid nanoparticles (SLNs) were prepared using a micro-emulsion technique and further optimized via Box-Behnken Design (BBD), considering key formulation variables including Glyceryl Monostearate, Soya Lecithin, and Tween 80. Nanoparticles were charac-terized by in vitro drug release, drug loading, encapsulation efficiency, zeta potential, particle size, and polydispersity index (PDI). Cytotoxic efficacy against the HT-29 colorectal cancer cell line was evaluated using the Sulforhodamine B (SRB) assay. Results: The optimized SLN formulation exhibited a mean particle size of 115.41 nm, PDI of 0.202, and zeta potential of +23.1 mV, indicating stability and efficient cellular uptake. Drug loading and encapsulation efficiency were 10.2 ± 0.4% and 92 ± 3.2%, respectively. In vitro release studies showed sustained drug release, reaching 97% over 48 hours. Cytotoxicity as-says demonstrated enhanced efficacy of Oxaliplatin SLNs, with IC₅₀ values of 0.9751 μg/mL at 24 h and 1.168 μg/mL at 48 h, compared to free Oxaliplatin (52.95 μg/mL at 24 h and 16.33 μg/mL at 48 h). Discussion: GMS-based SLNs optimized with Tween 80, lecithin, and DDAB exhibited ideal size, charge, and high encapsulation. FTIR and DSC analyses confirmed component compat-ibility. The formulation showed sustained release and enhanced cytotoxicity, highlighting its potential to improve Oxaliplatin delivery and therapeutic efficacy in colorectal cancer. Conclusion: The optimized Oxaliplatin SLNs demonstrated improved solubility, controlled release, and enhanced cytotoxicity, confirming their promise as a nanocarrier system for col-orectal cancer therapy. Further in vivo studies are required to validate clinical effectiveness.
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