Rationale Design of a Liposomal Formulated Phenanthro[9, 10-d]imidazole-Based ZnII Complex as a Targeted Anticancer Unit

Abstract The development of targeted and multifunctional anticancer nanoplatforms remains challenging due to limited selectivity, systemic toxicity, drug resistance, and off-target effects associated with conventional platinum-based chemotherapy. Zn(II) complexes have emerged as promising low-toxicity metal-based alternatives, exhibiting enhanced cytotoxicity toward cancer cells compared to healthy cells. In this study, a Schiff base ligand (K) was synthesized via condensation of 4-(1H-phenanthro[9,10-d]imidazol-2-yl)aniline and salicylaldehyde followed by complexation with Zn(II) to form a Zn(II) complex (S1). To enhance site-specific cellular uptake, Zn(II) complex S1 was encapsulated within folic acid-functionalized 10,12-pentacosadiynoic acid (FA-PCDA) and 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC)-based liposomes via molecular co-assembly, significantly improving stability and targeting capability. The resulting liposomal formulation of Zn(II) complex S1 (Lip-S1) exhibited characteristic fluorescence properties, enabling potential imaging applications. Lip-S1 selectively targeted folate receptor-expressing cervical cancer (HeLa) cells, demonstrating enhanced anticancer efficacy with a half maximal inhibitory concentration (IC50) of 143.8 μg mL–1 compared to free S1 and bare liposomes. Functional assays revealed that Lip-S1 inhibited cell proliferation, migration, and tumor spheroid growth while inducing apoptosis through mitochondrial membrane depolarization, elevated intracellular reactive oxygen species (ROS), caspase 3/7 activation, and modulation of apoptotic proteins (Bax upregulation, Bcl-2 downregulation). ROS scavenging studies confirmed that apoptosis is primarily mediated by oxidative stress linked to the PI3K/AKT (phosphatidylinositol 3 kinase/protein kinase B) signaling pathway. Enhanced cellular internalization of Lip-S1 relative to controls was also observed. These results highlight Lip-S1 as a targeted, fluorescence-trackable nanoplatform for ROS-mediated anticancer therapy.