Metal-organic framework IRMOFs coated with a temperature-sensitive gel delivering norcantharidin to treat liver cancer

Figure 1 Structure and morphology of IRMOF-3 and norcantharidin-loaded metal-organic framework IRMOF-3 coated with temperature-sensitive gel. A: X-ray diffraction (XRD) spectra of IRMOF-3. Note: XRD patterns of synthetic IRMOF-3 (b) and standard IRMOF-3 (a). XRD patterns of the sample show the same peaks as those of the standard, confirming the high purity of IRMOF-3. The peak patterns of the sample account for the rough appearance of the nanosized particles; B: Scanning electron microscopy (SEM) images of the morphology of IRMOF-3. SEM images of the morphology of IRMOF-3. The particles show a regular square, uniform distribution and a size of 50-100 nm. The single-particle surface is rough, indicating the existence of pores; C: SEM images of the morphology of norcantharidin (NCTD)-loaded metal-organic framework IRMOF-3 coated with temperature-sensitive gel (NCTD-IRMOF-3-Gel). SEM images of the morphology of NCTD-IRMOF-3-Gel showing the same size as that of IRMOF-3; D: Nitrogen adsorption–desorption isotherms of IRMOF-3. Nitrogen adsorption–desorption isotherms. A hysteresis loop phenomenon appears under relatively high pressure, indicating the existence of channels in the sample; E: Particle size distribution of NCTD-IRMOF-3-Gel. The particle size distribution of NCTD-IRMOF-3-Gel indicated that the average particle size was 100 nm.

Figure 2 In vitro release curves of norcantharidin (NCTD) (blue line), NCTD-loaded metal-organic framework IRMOF-3 (red line), and NCTD-loaded metal-organic framework IRMOF-3 coated with temperature-sensitive gel (green line). After approximately 5 h, 90% of norcantharidin (NCTD) was found in the release medium, while only 50% of NCTD was released from NCTD-loaded metal-organic framework IRMOF-3 (NCTD-IRMOF-3), and 30% of NCTD was released from NCTD-loaded metal-organic framework IRMOF-3 coated with temperature-sensitive gel (NCTD-IRMOF-3-Gel). Every trial was repeated three times. All values are shown as the mean ± SD.

Figure 3 Comparison of the cytotoxicities of norcantharidin (NCTD), NCTD-loaded metal-organic framework IRMOF-3, and NCTD-loaded metal-organic framework IRMOF-3 coated with temperature-sensitive gel. The inhibitory effect of norcantharidin (NCTD)-loaded metal-organic framework IRMOF-3 coated with temperature-sensitive gel (NCTD-IRMOF-3-Gel) (C) on Hepa1-6 cells was stronger than that of NCTD (A) and NCTD-loaded metal-organic framework IRMOF-3 (NCTD-IRMOF-3) (B) and showed a certain sustained-release effect.

Figure 4 Effects of norcantharidin-loaded metal-organic framework IRMOF-3 coated with temperature-sensitive gel on the cell cycle. The percentage of total cells in S and G2/M phases increased significantly with increasing norcantharidin (NCTD)-loaded metal-organic framework IRMOF-3 coated with temperature-sensitive gel (NCTD-IRMOF-3-Gel) concentration, and the proportion of cells in G0/G1 phase decreased significantly. A: Control group; B: 10 μg/mL; C: 20 μg/mL; D: 40 μg/mL. G1 phase: DNA presynthetic phase, where mitosis is complete before DNA replication begins; G2 phase: DNA synthesis replication phase, where DNA replication is complete before mitosis begins; M phase: Cell division phase; S phase: DNA synthesis replication phase.

Figure 5 Apoptosis rates of Hepa1-6 cells after 48 h. Apoptosis rates of norcantharidin (NCTD)-loaded metal-organic framework IRMOF-3 coated with temperature-sensitive gel (NCTD-IRMOF-3-Gel) at the high concentration (C) and low concentration (F) were 32.11 μg/mL and 65.60 μg/mL, respectively. Compared with the NCTD control group, the apoptosis rate in the NCTD-IRMOF-3-Gel group was highest, which indicated that NCTD-IRMOF-3-Gel could induce the apoptosis of Hepa1-6 cells. A: 50 μg/mL NCTD-IRMOF-3; B: 50 μg/mL NCTD; C: 50 μg/mL NCTD-IRMOF-3-Gel; D: 25 μg/mL NCTD-IRMOF-3; E: 25 μg/mL NCTD; F: 25 μg/mL NCTD-IRMOF-3-Gel.

Figure 6 Apoptosis rates of norcantharidin (NCTD), NCTD-loaded metal-organic framework IRMOF-3, and NCTD-loaded metal-organic framework IRMOF-3 coated with temperature-sensitive gel. Compared with the norcantharidin (NCTD) control group, the apoptosis rate in the NCTD-loaded metal-organic framework IRMOF-3 coated with temperature-sensitive gel (NCTD-IRMOF-3-Gel) group was highest, which indicated that NCTD-IRMOF-3-Gel can induce the apoptosis of Hepa1-6 cells.