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Page 2 of 18 Wang et al. Cancer Drug Resist. 2026;9:8

Research and Evaluation of Pharmaceutical Preparations, Guangdong Pharmaceutical University, Guangzhou 510006, Guangdong, China.
E-mail: yht193525@163.com

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.

INTRODUCTION
Chemotherapy stands as a pivotal tool in the arsenal of cancer therapeutics, particularly for mid-to-late-stage
tumors with high metastatic potential . However, the emergence of multidrug resistance (MDR) in tumor
[1]
cells, which contributes to over 90% cancer-related fatalities, remains a significant challenge in cancer
therapy [2-4] . This underscores the urgent need to address this persistent issue to improve patient survival
outcomes.

One key role in cancer drug resistance is the lysosome , which not only degrades chemotherapeutic agents
[5-9]
through enzymatic hydrolysis but also sequesters them away from their intracellular targets, effectively
reducing the active drug concentration [10,11] . Lysosomal drug sequestration is particularly relevant for
weak-base chemotherapeutics - such as doxorubicin (DOX) - through ion trapping, thereby impairing drug
access to nuclear targets and promoting resistance . To overcome this, strategies inducing lysosomal
[12]
membrane permeabilization (LMP) have been developed, primarily through either physical membrane
disruption (e.g., in-situ self-assembling peptides, cationic amphiphilic drugs) [13-15] or reactive oxygen species
(ROS)-mediated chemical degradation (e.g., ferroptosis inducers, nanozymes) [16-18] . However, many of these
approaches lack specific lysosome membrane targeting ability, and rely on single mechanisms or complex
nanomaterials [19,20] , which may limit their efficacy and translational potential. Thus, designing a simple
molecular material capable of lysosome membrane targeting for dual-mode function modulation is
particularly crucial.

Membrane-intercalating conjugated oligoelectrolytes (MICOEs) emerge as an ideal candidate to tackle this
challenge. Characterized by a linear π-conjugated backbone and positively charged side chains at both ends,
MICOEs can form stable assemblies with lipid membranes through synergistic hydrophobic and electrostatic
interactions [21,22] . This intercalation can be utilized to finely tune cell membrane permeability to small
molecules by adjusting the distance between the charges of MICOEs [23-26] . Furthermore, the conjugated
backbone endows MICOEs with excellent photoactivity, enabling efficient light-induced in-situ membrane
disruption [27,28] . This unique combination of membrane-embedding capability and light-induced reactivity
makes MICOEs a quintessential molecular platform for dual-mode membrane modulation.

With these points in mind, we developed a novel lysosome-targeting MICOE photosensitizer, PTTP-DC6, to
recover anticancer activity of a conventional chemotherapeutic drug (DOX) in MDR cancer cells. As

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