ECM-responsive PEGylated liposomal biomaterial for enhanced tumor penetration through Dual-Mechanism microenvironment...

This study aimed to develop a self-facilitating PEGylated liposomal system co-delivering ceritinib (anticancer) and telmisartan (antifibrotic) to overcome the extracellular matrix (ECM) barrier limiting therapeutic efficacy in solid tumors. Dual drug-loaded liposomes were prepared by thin film hydration using an optimized 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC):cholesterol:1,2-distearoyl-sn-glycero-3-phosphoethanolamine-polyethylene glycol 2000 (DSPE-PEG(2000)) ratio (6:1:0.1). Formulations were characterized for particle size, zeta potential, drug encapsulation, and release kinetics. Physicochemical characteristics were evaluated using differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and Fourier transform infrared spectroscopy (FTIR). Therapeutic efficacy was assessed in A549 lung cancer cells and A549 xenograft mouse models. The optimized formulation exhibited nanoscale dimensions (77.7 ± 3.54 nm) with a zeta potential of -23.9 ± 8.73 mV and high encapsulation efficiencies for ceritinib (69.61 ± 2.30 %) and telmisartan (63.43 ± 1.12 %). Drug release followed Korsmeyer-Peppas kinetics (R² > 0.98) with diffusional exponents of 0.45-0.48. The liposomal system demonstrated remarkable stability for 12 months under refrigeration with < 18 % size increase and > 89 % drug retention. In vivo studies revealed 4.85-fold greater tumor reduction compared to ceritinib-only liposomes, with 67.3 ± 5.2 % reduction in collagen density creating enhanced penetration pathways. Caspase-3/7 assays confirmed 5.3-fold increased apoptotic activity. The dual drug-loaded PEGylated liposomal system offers a promising pharmaceutical platform for overcoming ECM barriers in cancer therapy, with excellent stability characteristics and significant advantages over conventional approaches.