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  • To demonstrate the MRI contrast ability in vivo

    2019-09-23

    To demonstrate the MRI Elafibranor (GFT505) ability in vivo, Gd-DTPA, Fe3O4, 
    Mn2+, [email protected] Fe3O4, and MFNP Elafibranor (GFT505) were injected into tumor-bearing nude mice with a dosage of 2 mg/kg via the tail vein, respectively. T1-and T2-weighted MR images of the tumor region were acquired at pre-injection and post-injection 15, 30, 60, 90, and 120 min (Fig. 7). T1-weighted images of tumor injected with Mn2+ slightly brightened at post-injec-tion 30 min, but significantly brightened for Gd-DTPA and MFNP, im-plying that MFNP and Gd-DTPA had a better contrast effect than Mn2+ ions (Fig. 7a). In addition, it could be seen that the brightest MR images of Gd-DTPA appeared at post-injection 30 min, but MFNP appeared at post-injection 90 min, which suggested that MFNP had a longer reten-tion time and could be a better MRI contrast agent in comparison with Gd-DTPA. In addition, analysis of the MRI signal-to-noise ratio change ( SNR) in the tumor region indicated that the highest SNR of Gd-DTPA, Mn2+, and MFNP was 65.1%, 41.8%, and 66.8% (Fig. 7b), suggesting that MFNP could be effectively accumulated in tumor and had a similar contrast ability in comparison with commercial contrast agent. For T2-weighted MR images, Tumor sites of the mice treated with [email protected] showed a slight reduction of signals and reached the re-lative weak dark MR images (Fig. 7c). Meanwhile, both Fe3O4 and MFNP presented strong contrast ability, and made tumor images dis-tinctly darkened. These results indicated that MFNP and Fe3O4 had stronger T2 contrast effect than [email protected] The corresponding highest SNR in T2 imaging were respectively 44.6%, 44.1%, and 33.6% for Fe3O4, MFNP, and [email protected] (Fig. 7d). These results suggested that MFNP could be a good T2 contrast agent as Fe3O4. Ad-ditionally, a decrease in SNR of T1 and T2 imaging appeared at 90 min p.i. for MFNP, indicating that MFNP began to be gradually excreted out from tumor tissue. These results indicated that among the systems tested, MFNP had excellent T1-T2 dual mode contrast ability and could be an ideal dual-mode MRI contrast agent.
    2.5. Investigation of antitumor effect of the nanoplatform
    The biocompatibility of MFNP was investigated by assessing HK-2 cell viability. No significant decrease in the viabilities of HK-2 cells was observed after incubation with a wide range of MFNP
    Fig. 8. (a) Viability of HK-2 cells treated with MFNP for 24 h. (b) Viability of HeLa cells treated with MFNP, free CDDP, and [email protected] for 24 h. (c) Relative tumor volume, (d) body weight, (e) representative images, and (f) excised tumors of mice subjected to different treatments. (g) Biodistribution analysis after intravenous injection of MFNP into mice at various time. (h) IHC and H&E staining of tumors in mice subjected to different treatments.
    concentrations for 24 h (Fig. 8a), implying that MFNP had good bio-compatibility for normal cells. This good biocompatibility was because the pH of normal cells is weakly alkaline and cannot induce the gen-eration of ·OH. Nevertheless, HeLa cells incubated with MnSiO3 and MFNP presented a dosage-dependent apoptosis, which might be be-cause MnSiO3 and MFNP could catalyze the generation of ·OH and cause cell apoptosis. Moreover, MFNP showed a stronger inhibition effect in comparison with MnSiO3, suggesting that the ·OH generation amount of HeLa cells induced by MFNP was higher than that of MnSiO3 (Fig. S7). Besides, the cellular apoptosis induced by free CDDP, and [email protected] was proportional to the incubated dose (Fig. 8b). The ability to kill HeLa cells was followed the order [email protected] > CDDP > MFNP, indicating that [email protected] had excellent the combined ability of catalytic nanotherapeutics and chemotherapies for overcoming cancer.
    Tumor volumes of mice treated with saline, MFNP, free CDDP, or [email protected] were used to assess therapeutic effect. As shown in Fig. 8c, tumor volume of mice treated with saline dramatically in-creased within 30 days. Nevertheless, tumor volume was slightly de-creased at post-injection of MFNP, which was because Mn and Fe ions