Conjugated oligoelectrolytes overcome cancer drug resistance by dual-mode lysosomal membrane disruption

Aim: Multidrug resistance (MDR) often arises from lysosomal sequestration of chemotherapeutics. This study aims to design and evaluate lysosome-targeting membrane-intercalating conjugated oligoelectrolytes (MICOEs) for their potential to reverse MDR via dual-mode lysosomal membrane disruption, and to identify the most effective candidate. Methods: Three MICOEs featuring a pyridothiadiazole-thienothiophene-pyridothiadiazole (PTTP) conjugated backbone with quaternary ammonium-terminated 4-, 6-, and 8-carbon alkyl chains at both ends (PTTP-DC4, PTTP-DC6, PTTP-DC8) were synthesized and characterized. Their photophysical properties, cellular uptake, and sublocalization were assessed in doxorubicin (DOX)-resistant Michigan Cancer Foundation-7/adriamycin-resistant (MCF-7/ADR) cells. Lysosomal integrity and contents release were evaluated via acridine orange and cathepsin B assays. Proteomic analysis was performed to uncover mechanisms. The combinational effect of PTTP-DC6 and DOX was tested in drug-resistant two-dimensional (2D) and three-dimensional (3D) cell models. Results: Among PTTP-DCns (where n = 4, 6, and 8, corresponding to PTTP-DC4, PTTP-DC6, and PTTP-DC8), PTTP-DC6 showed optimal lysosomal accumulation and induced lysosomal membrane permeabilization (LMP) through both physical membrane interaction and light-triggered reactive oxygen species generation. Proteomic analysis revealed significant enrichment of pathways associated with oxidative stress and lysosomal dysfunction. Pretreatment with PTTP-DC6 at low doses, particularly under mild light irradiation, significantly enhanced DOX sensitivity in resistant 2D monolayers and 3D spheroid models. Conclusion: PTTP-DC6 overcomes MDR by dual-mode LMP induction, providing a simple strategy to resensitize resistant cancers to conventional chemotherapy.