Development of Pectin-Coated Cationic Liposomes for Sustained Drug Release, Enhanced Serum Stability and Reduced Macrophage Uptake

Background: Cationic liposomes are promising carriers for anticancer agents but are often limited by rapid clearance by the mononuclear phagocyte system, poor serum stability, and insufficient control of drug release. This study aimed to develop and characterize pectin-coated, Ca2+-crosslinked cationic liposomes as a multifunctional delivery platform providing sustained release, enhanced serum stability, and reduced macrophage uptake while preserving the biological activity of an encapsulated anticancer compound. Methods: The optimal polysaccharide-to-liposome ratio was established by ζ-potential polyelectrolyte titration, and coating parameters were optimized using a Taguchi experimental design. Physicochemical characterization included dynamic light scattering (DLS), transmission electron microscopy (TEM), isothermal titration calorimetry (ITC), small-angle X-ray scattering (SAXS), and differential scanning calorimetry (DSC). The optimized formulations were further evaluated for drug release, serum stability, cellular uptake and cytotoxicity against A549 and HeLa cells using MTT and Neutral Red assays. Results: Polyelectrolyte titration identified a pectin-to-liposome saturation ratio of 3:1, and Taguchi optimization yielded a formulation with a drug retention efficiency of 99.34%. Pectin coating significantly reduced the initial burst release (37.9% at 1 h) and decreased cumulative drug release after 48 h (66.3%), consistent with a polymer relaxation-controlled release mechanism. The coated liposomes also exhibited enhanced serum stability and reduced macrophage uptake (up to ~73% lower in RAW264.7 cells), while maintaining uptake by non-phagocytic cells. The biological activity of the encapsulated model compound was preserved, with enhanced cancer-cell selectivity against A549 and HeLa cells demonstrated by both MTT and Neutral Red assays. Conclusions: Pectin-Ca2+ surface functionalization transforms cationic liposomes into a stable sustained-release delivery platform with reduced macrophage recognition and enhanced serum stability. These findings support the further development of this carrier as a versatile platform for the systemic delivery of anticancer agents.