Zeolitic Imidazolate Framework‐8 as pH‐Sensitive Nanocarrier for “Arsenic Trioxide” Drug Delivery

Abstract Previous results revealed that arsenic trioxide might be used as promising therapeutic agent for the treatment of some solid tumours as atypical teratoid rhabdoid tumours (ATRT). However, in order to become an approved drug for solid tumour treatment, the active formulation has to get more efficient and feasible—but at the same time less toxic. One of the possibilities to achieve this dichotomy is to use nanomedicine tools. Herein, we report on the Zn‐based metal–organic framework ZIF‐8 (Zeolitic Imidazolate Framework‐8) which turned out to be a promising candidate for the delivery of AsIII species. It conjointly features a high drug loading capacity and a prominent pH‐triggered release behaviour. AsIII‐loaded ZIF‐8 nanoparticles coated and non‐coated with polyethylene glycol were studied by XRPD, IR, Raman, TGA, TEM, EDX, CHN‐elemental analysis, sorption analysis and ICP‐OES, and their cytotoxicity was evaluated in vitro.


Computational modelling
In order to simulate the crystal structure and vibrational properties of As@ZIF-8, first principle DFT+D lattice geometry optimizations were performed with the CASTEP code, 1 PBE-GGA, onthe-fly generated norm-conserving plane-wave pseudopotentials (energy cutoff: 1380 eV) employing a semi-empirical dispersion correction for non-bonding interactions according to the scheme suggested by Tkatchenko and Scheffler. 2,3 The final lattice parameters and selected properties of the fully converged cell showing the best match with the experimental vibrational frequencies is shown in Table S2. A lattice model of the geometry-converged unit cell of this compound is displayed in Figure S8. Phonon frequencies were obtained via CASTEP DFPT linear response calculations at the  points of the converged primitive cell geometries. 4 Selected calculated frequencies are presented in Table S2 together with an assignment to characteristic (localized = vibrational) modes. The calculated and measured IR spectra were compared and fitted with SpecDis version 1.71 software. 5 Herein, a scaling factor of 1.003 was applied and the intensity of the calculated spectra was divided by a factor of 65 and 20 in the range of 1800-200 cm -1 and 800-200 cm -1 , respectively. Transmittance / a.u.

Drug release and MOF stability studies
Drug release followed over 7 days  Figure S13. FTIR spectra of PEG-NH 2 @As@ZIF-8 (black) and PEG-NH 2 @As@ZIF-8 after the arsenic release studies carried out at pH 6 for 1 h (red), 24 h (blue), 48 h (green), 72 h (purple) and 168 h (orange) displayed in the area from 1800 to 400 cm -1 .

for 1 h (red), 24 h (blue), 24 h (green), 72 h (purple) and
168 h (orange) (samples were activated at 100 °C for 3 h and exposed to a flow of nitrogen gas). and 168 h (orange) (samples were activated at 100 °C for 3 h and exposed to a flow of nitrogen gas).

S12
MOF stability in phosphate buffered saline at pH 6 followed over 7 days X-ray powder diffraction (XRPD) measurements:  h (orange) (samples were activated at 100 °C for 3 h and exposed to a flow of nitrogen gas). and 168 h (orange) (samples were activated at 100 °C for 3 h and exposed to a flow of nitrogen gas).

Cytotoxicity studies
The composition of the nanoparticles of As@ZIF-8 and PEG-NH 2 @As@ZIF-8 was determined by ICP-OES ( c Amount of ZIF-8 which can be loaded with As-amount corresponding to the given concentration of As 2 O 3 (0.0001  100 µM). d Amount of 2-methylimidazole in ZIF-8 which can be loaded with As-amount corresponding to the given concentration of As 2 O 3 (0.0001  100 µM). S16 Figure S22. Cell viability of (a) fibroblasts, (b) BT12-and (c) BT16 cells after 24 h of incubation with increasing concentrations of ZIF-8 (black), As@ZIF-8 (red) and PEG-NH 2 @As@ZIF-8 (blue). The given concentration corresponds to the concentration of As 2 O 3 (0 -100 µM) which was effectively loaded or could be theoretically loaded (for details see Table S4). Data are presented as mean ± S.E.M (n ≥ 3).

Figure S23. Cell viability of (a) BT12-and (b) BT16 cells after 24 h of incubation with increasing
concentrations of ATO (grey), As@ZIF-8 (red) and PEG-NH 2 @As@ZIF-8 (blue). The given concentration corresponds to the concentration of As 2 O 3 (0 -100 µM) which was effectively loaded or could be theoretically loaded (for details see Table S4). Data are presented as mean ± S.E.M (n ≥ 3).