A Redox Cleavable and Targeting Nanoassembly Based on CPT/DOXY Conjugates for Synergistically Enhanced Chemo/Photodynamic/Photothermal Combined Tumor Therapy

Combined use of different drugs and therapy modes has been effective in improving tumor therapy efficiency and reducing side effects. However, synergistic anticancer efficiency and highly responsive drug release still remain challenging. Herein, we found that camptothecin (CPT), doxycycline (DOXY), and IR780 exhibit a synergistic anticancer effect on CT26 colorectal cancer cells. Thereafter, a redox dual-responsive CPT/DOXY hybrid dimer, CPT-SeSe-DOXY, was synthesized via the –SeSe– linkage. As a control, CPT-SS-DOXY was also synthesized. Both dimers were able to self-assemble with IR780 and DSPE-PEG-iRGD into multifunctional, stimuli-responsive, aqueous-dispersible, and spherical nanoparticles (NPs) with diameters of 83–87 nm. The C-SeSe-D/I/RGD NPs showed significantly stronger responsiveness to glutathione, H2O2, and near-infrared (NIR) lasers, reflected by dramatically higher responsive drug release ratios and stronger generation of 1O2 upon NIR laser irradiation, than the C–SS–D/I/RGD NPs. They can be highly taken up by CT26 cells, while hardly taken up by normal colorectal cells. In addition, they exhibited a very efficacious killing property against CT26 cells. The cell viability with C-SeSe-D/I/RGD NPs (with NIR laser) at 4.0 μg·mL–1 equivalent CPT at hypoxic conditions reached as low as ∼7.8%. The treatment can induce strong mitochondrial depolarization, ATP depletion, reactive oxygen species (ROS) generation, and therefore high cell apoptosis, even in hypoxic cultures. They can highly accumulate in tumors and lead to as high as 90.8% tumor growth inhibition under an NIR laser. Collectively, the C-SeSe-D/I/RGD NPs possess sensitive multistimuli-responsive capabilities and efficacious chemo/photothermal/photodynamic combined tumor therapy, exhibiting great potential in clinical applications.