Smart Cu(II)-aptamer complexes based gold nanoplatform for tumor micro-environment triggered programmable intracellular prodrug release, photodynamic treatment and aggregation induced photothermal therapy of hepatocellular carcinoma

Abstract

This study describes smart Cu(II)-aptamer complexes based gold nanoplatform for tumor micro-environment triggered programmable prodrug release, in demand photodynamic therapy and aggregation induced photothermal ablation of hepatocellular carcinoma. The nanoplatform is consist of monodispersed gold nanoparticle (GNP) that is binding to HCC cell specific targeting aptamers (TLS11a) through Au-S bond; the aptamer is labeled with Ce6 at the 5'end and coordinated with Cu(II) through (GA) 10 repeating bases to load AQ4N at the 3' end. In normal physiological conditions, the fluorescence and ROS generation ability of Ce6 are quenched by GNPs via RET; but in cancerous cells, the fluorescence and the ROS generation of Ce6 could be recovered by cleavage of Au-S bond through high level of intracellular GSH for real-time imaging and in demand PDT. Meanwhile, the prodrug AQ4N release could be triggered by acid-cleavage of coordination bonds, then accompanied by a release of Cu(II) that would induce the electrostatic aggregation of GNPs for photo-thermal ablation; furthermore, the significantly enhanced chemotherapy efficiency could be achieved by PDT produced hypoxia to convert AQ4N into AQ4. In summary, here described nanoplatform with tumor cell specific responsive properties and programmable PDT/PTT/chemotherapy functions, might be an interesting synergistic strategy for HCC treatment.

Chemotherapeutic Drug Based Metal–Organic Particles for Microvesicle‐Mediated Deep Penetration and Programmable pH/NIR/Hypoxia Activated Cancer Photochemotherapy

“…These results clearly proved that the ZnPC‐ADMOPs could selectively produce ROS upon laser irradiation. To further confirm that the PDT selectively induced local hypoxia in HepG2 cells, which is crucial for enhancing the chemotherapy efficiency of AQ4N, a hypoxia detection probe (MitoXpress Kit) was used 27, 28. As shown in Figure 5d, much stronger fluorescence (red color) was observed by CLSM in ZnPC‐ADMOP‐treated HepG2 cells upon laser irradiation, indicating a high level of PDT‐induced hypoxia in the environment.…”

“…Liver cancer cells (HepG2) were treated with free DOX, free AQ4N, Cu(II) ions or the ADMOPs for 48 h. As shown in Figure S10 (Supporting Information), free DOX alone (22.52 µg mL −1 ) induced relatively high toxicity in HepG2 cells (with 35.2% of cell viability), which was consistent with reports in the literature. In contrast, the viability of cells treated with free AQ4N alone (9.36 µg mL −1 ) was as high as 94%, which might due to the lack of toxicity of AQ4N in aerobic conditions 27, 31. Interestingly, Cu(II) alone also exerted a certain degree of cytotoxicity (with 69.2% of cell viability), which was lower than free DOX but higher than free AQ4N.…”

“…As the incubation time progressed, both AQ4N fluorescence and DOX fluorescence were concomitantly increased in the cytoplasm of HepG2 cells. To further investigate the uptake efficiency of our ADMOPs, HepG2 cells were treated with free DOX, free AQ4N, and the ADMOPs for 4 h. As shown in Figure 3d, the fluorescence intensity of AQ4N (red) from the ADMOP‐treated cells was much higher than that of free AQ4N‐treated HepG2 cells, indicating that the nanoscale‐sized ADMOPs could be more efficiently uptaken via endocytosis than neutral free AQ4N via diffusion,27, 28 However, the fluorescence intensity of DOX (green) from the ADMOP‐treated cells was slightly lower than that from the free DOX‐treated cells and exhibited a different cellular distribution pattern compared with free DOX. As shown in Figure 3d,e, the DOX signal from ADMOP‐treated cells was mostly located in lysosomes near the nucleus, while the DOX signal of free DOX‐treated cells was mostly located in the nucleus (Figure 3d).…”

“…Previous evidence has suggested that the reduction of AQ4N to toxic AQ4 could be enhanced by increasing the local hypoxic level of tumors to further increase cancer cell killing 27, 33. Inspired by this possibility, we attempted to load the ADMOPs, which has inherent porous characteristics and can dynamically respond to specific tumor environments, with a hydrophobic photosensitizer (ZnPC).…”

“…Then, 50 µL fresh medium containing the ROS fluorescence indicator (2,7‐dichlorofluorescein diacetate, DCFH‐DA) was added to the 96‐well plates, followed by adding 100 µL oil (nontoxic) to the upper surface of the medium ( Figure 5 a,b) 27. Under 670 nm laser irradiation, the ZnPC‐ADMOP‐treated HepG2 cells exhibited significantly stronger green fluorescence compared with ZnPC‐ADMOP‐ and ADMOP‐treated cells without laser irradiation or untreated HepG2 control cells (Figure 5c).…”