ECM-responsive PEGylated liposomal biomaterial for enhanced tumor penetration through Dual-Mechanism microenvironment remodeling in lung cancer

Rajeshkumar S Palva; Jolly R Parikh; Rajnikant M Suthar; Musaratafrin Saiyed; Mitali Patel; Prajesh Prajapati; Umang H Shah

doi:10.1016/j.ijpharm.2025.125805

ECM-responsive PEGylated liposomal biomaterial for enhanced tumor penetration through Dual-Mechanism microenvironment remodeling in lung cancer

Int J Pharm. 2025 Jun 2:681:125805. doi: 10.1016/j.ijpharm.2025.125805. Online ahead of print.

Authors

Rajeshkumar S Palva¹, Jolly R Parikh², Rajnikant M Suthar², Musaratafrin Saiyed³, Mitali Patel⁴, Prajesh Prajapati⁵, Umang H Shah⁶

Affiliations

¹ Department of Pharmaceutics, Gujarat Technological University, Ahmedabad, Gujarat, India. Electronic address: rajeshpalva@gmail.com.
² Department of Pharmaceutics, A.R. College of Pharmacy and G H Patel Institute of Pharmacy, Vallabh Vidyanagar, Gujarat, India.
³ Department of Pharmacology, A.R. College of Pharmacy and G H Patel Institute of Pharmacy, Vallabh Vidyanagar, Gujarat, India.
⁴ Department of Pharmaceutics, Maliba College of Pharmacy, Uka Tarsadia University, 394350, Gujarat, India.
⁵ School of Pharmacy, National Forensic Sciences University, Gandhinagar, Gujarat, India.
⁶ Ramanbhai Patel College of Pharmacy, Charotar University of Science and Technology (CHARUSAT), CHARUSAT Campus, Changa 388421, India.

PMID: 40466878
DOI: 10.1016/j.ijpharm.2025.125805

Abstract

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.

Keywords: Controlled release; Dual drug-loaded liposomes; Freeze-dried formulation; Long-term stability; PEGylated delivery system; Pharmaceutical nanocarriers.