ATP-triggered mitochondrial cascade reactions for cancer therapy with nanoscale zeolitic imidazole framework-90

Abstract

Goals: Chemotherapy, the most conventional modality for cancer therapy, usually brings serious side effects because of the low cancer-therapeutic specificity and bioavailability. It is of great significance for cancer treatment to develop new effective strategies to regulate biochemical reactions in organelles, enhance the specificity of chemotherapeutic drugs and reduce their side effects. Methods: We report herein a zeolitic imidazole framework-90 (ZIF-90) based nanoplatform, which was used to initiate a series of mitochondrial cascade reactions using ATP as a molecular switch for cancer therapy. The thioketal linked camptothecin (camptothecin prodrug, TK-CPT) and 2-Methoxyestradiol (2-ME) were encapsulated into the pores of ZIF-90 nanoparticles using a simple one-pot method, and the nanoplatform was finally coated with a layer of homologous cell membrane. Results: Mitochondrial ATP can efficiently degrade ZIF-90 and then release the loaded 2-ME and CPT prodrugs. 2-ME can inhibit the activity of superoxide dismutase (SOD), which induces the up-regulation of reactive oxygen species (ROS) in situ. The thioketal linkers in CPT prodrug can respond to ROS, thereby achieving subsequent release of parent CPT drug. This cascade of reactions can lead to prolonged high oxidative stress and cause continuous cancer cell apoptosis, due to the increased ROS level and the liberation of CPT. Conclusion: We constructed an ATP-triggered strategy using nanoscale ZIF-90 to initiate mitochondrial cascade reactions for cancer therapy. The ZIF-90 based nanoplatform exhibited low cytotoxicity, good mitochondria-targeting ability, and excellent therapeutic effect. In vivo experiments demonstrated that the growth of tumor can be efficiently inhibited in a mouse model. This ATP-triggered strategy to induce mitochondrial biochemical reactions offers more possibilities for developing organelle-targeted therapeutic platforms.

Keywords: 2-methoxyestradiol; ATP; camptothecine; reactive oxygen species; zeolitic imidazole framework-90.

Scheme 1

Schematic illustration of the preparation of the ZIF-90 based platform and cancer treatment processes.

Figure 1

(A) TEM images of ZIF-90, MZ, TZ, MTZ, and MTZ@C. Scale bars are 100 nm. (B) Hydrodynamic size distributions of different nanoparticles. (C) Zeta potentials of different nanoparticles. (D) N₂ adsorption-desorption isotherms of ZIF-90 and MTZ. (E) UV-vis spectra of ZIF-90, TK-CPT, 2-ME, and MTZ.

Figure 2

(A) Photograph of MTZ aqueous solution (5 mg/mL) without (left) or with (right) ATP (10 mg/mL) within 5 min. (B) TEM images of MTZ (0.5 mg/mL) at different intervals (30 s, 1 min and 2 min) after the addition of ATP (1 mg/mL). Scale bars are 100 nm. (C) Release rate of TK-CPT from the ZIF-90 framework (5 mg/mL) under different ATP conditions within 5 min. (D) HPLC analysis of TK-CPT upon 24 h incubation with O₂^·-.

Figure 3

(A) Mitochondrial co-location images of MTZ@C nanoparticles incubated with 4T1 cells for different time. The cells were incubated with the probe mito-tracker green before confocal imaging. (B) The relative activity level of SOD in cells after incubation with different nanoparticles. Data were presented as the mean ± SD (n = 3), **P < 0.01, ***P < 0.001. (C) MTT assay of 4T1 cells with different treatments. Data were presented as the mean ± SD (n = 3), **P < 0.01, ***P < 0.001. (D) Confocal images of calcium AM and PI stained 4T1 cells after different treatments. Scale bars are 100 µm. (E) Confocal images of 4T1 cells after treated with PBS, ZIF-90@C, TZ@C, MZ@C, and MTZ@C. The cells were incubated with the probe DCFH-DA before confocal imaging.

Figure 4

(A) Diagrammatic representation of the therapeutic experiment. (B) Photographs of dissected tumors after the mice were treated with different materials for 14 days. (C) Photographs of the mice taken before treatment (0 days) and at the 14^th day with different treatments. (D) Tumor growth curves within 14 days after the mice were received different treatments. Data were presented as the mean ± SD (n = 5), **P < 0.01.