Electrostatically engineered fucoidan-coated liposomal oxaliplatin: In silico, 2D 3D, in vivo pharmacokinetic evaluations for colorectal cancer management.

Oxaliplatin (OXP), a third-generation platinum chemotherapeutic, is widely used in colorectal cancer (CRC) therapy as a key component of the FOLFOX4 (folinic acid, fluorouracil, and oxaliplatin) regimen. However, its clinical utility is limited by dose-dependent toxicity, poor intracellular uptake, and drug resistance. To address these limitations, fucoidan-functionalized oxaliplatin-loaded liposomes (OX-CH-FC-Lipo) were developed to enhance the therapeutic performance of oxaliplatin by exploiting the reported affinity of fucoidan for P-selectin. Molecular dynamics simulations demonstrated stable and sustained interactions of fucoidan with CRC-associated proteins. The OX-CH-FC-Lipo were fabricated by sequential coating of oxaliplatin-loaded Phospholipon® 90G liposomes with chitosan and fucoidan, exhibiting a mean particle size of 219 ± 3.28 nm, a polydispersity index of 0.30 ± 0.02, and a zeta potential of -11.98 ± 0.41 mV. The liposomal formulation exhibited sustained drug release over 24 h at physiological pH 7.4. OX-CH-FC-Lipo demonstrated nearly six-fold greater cytotoxicity than free OXP, accompanied by enhanced intracellular reactive oxygen species generation, disruption of mitochondrial membrane potential, and inhibition of cell migration in HCT-116 cells. Western blot analysis further confirmed apoptosis through modulation of the Bax/Bcl-2 ratio. In vivo pharmacokinetic evaluation demonstrated approximately seven fold improved oral bioavailability, controlled Cmax, prolonged systemic exposure, and reduced systemic toxicity compared with free OXP. Collectively, these findings highlight OX-CH-FC-Lipo as a promising fucoidan-functionalized liposomal nanocarrier for colorectal cancer therapy.