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Wang et al. Cancer Drug Resist. 2026;9:8 Page 13 of 18

Figure 6. PTTP-DC6 enhances DOX efficacy in drug-resistant cells and spheroids. (A) Cytotoxicity of DOX to MCF-7/ADR cells after
PTTP-DC6 (1 μM, 24 h) treatment under dark or light irradiation (525 nm, 0.2 mW·cm , 30 min) (one-way ANOVA with Tukey’s test,
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*** P < 0.001); (B) Relative viability rates of PTTP-D6-treated group under dark or light irradiation referring to viabilities of control group
treated with DOX only. V: The cell viability of combinations, V DOX : the cell viability of DOX only, V0, V DOX,0 : the cell viability in the 0 μM DOX
group; (C) In vitro cytotoxicity of DOX (100 μg·mL ) to MCF-7/ADR cell spheroids for 48 h with or without the pretreatment of PTTP-DC6
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(5 μM, 24 h) and the followed irradiation of a 525 nm LED light (1 mW·cm , 30 min) (one-way ANOVA with Tukey’s test, P < 0.001);
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***
(D) Representative bright-field images of MCF-7/ADR cell spheroids with different treatments on day 0 and day 3. Scale bar: 200 µm; (E)
Corresponding SEM images of MCF-7/ADR cell spheroids of various treatment conditions on day 3. Scale bar: 10 µm. Data presented as
mean ± SD. PTTP-DC6: Benzene-pyridothiadiazole-thienothiophene-pyridothiadiazole-benzene conjugated framework with quaternary
ammonium-terminated C6 alkyl chains at both ends; DOX: doxorubicin; MCF-7/ADR: Michigan Cancer
Foundation-7/adriamycin-resistant; ANOVA: analysis of variance; LED: light emitting diode; SEM: scanning electron microscope; SD:
standard deviation.

Recovering anticancer activity of DOX in MDR cancer cells and spheroids
We first evaluate the ability of PTTP-DCns to reverse drug resistance in cancer cells using the MTT assay.
The viabilities of MCF-7/ADR cells treated with DOX at various concentrations and 1 μM PTTP-DCns
under dark or light irradiation were tested [Figure 6A, Supplementary Figure 11A and B]. With the viabilities
of cells treated with DOX only in the dark as references, the corresponding ratios were calculated for
quantitative analysis [Figure 6B, Supplementary Figure 11C and D]. PTTP-DC6 and PTTP-DC8 exhibited
the ability to recover drug sensitivity of MCF-7/ADR cells under light, while PTTP-DC4 did not possibly due
to weak association [Supplementary Figure 8]. However, only PTTP-DC6 decreased the cell viability under
dark. As shown in Figure 6B, the introduction of PTTP-DC6 decreased the viability of cells treated with
100 μg·mL DOX by 19% in the dark, and additional light processing further decreased the viability by 68%.
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The half-maximal inhibitory concentration (IC ) for DOX in PTTP-DC6 pre-treated MCF-7/ADR cells
50
under light decreased to 48.6 μg·mL , with a resistance index (RI) decreasing from 39 to 19.
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In addition, we compared the resensitization efficacy and cytotoxicity of PTTP-DC6 with CQ, a classical
lysosomal disruptor [Supplementary Figure 12]. Although CQ showed a stronger resensitization effect than
PTTP-DC6 treatment in the dark, the combination of PTTP-DC6 with light achieved the highest efficacy.
Notably, CQ exhibited significant cytotoxicity at 1 μM. To further validate the mechanistic specificity of our

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