Abstract
The three-dimensional (3D) microporous titanium aminoterephthalate MIL-125-NH2 (MIL: Material of Institut Lavoisier) was successfully isolated as monodispersed nanoparticles, which are compatible with intravenous administration, by using a simple, safe and low-cost synthetic approach (100 °C/32 h under atmospheric pressure) so that for the first time it could be considered for encapsulation and the release of drugs. The nerve agent antidote 2-[(hydroxyimino)methyl]-1-methyl-pyridinium chloride (2-PAM or pralidoxime) was effectively encapsulated into the pores of MIL-125-NH2 as a result of the interactions between 2-PAM and the pore walls being mediated by π-stacking and hydrogen bonds, as deduced from infrared spectroscopy and Monte Carlo simulation studies. Finally, colloidal solutions of MIL-125-NH2 nanoparticles exhibited remarkable stability in different organic media, aqueous solutions at different pH and under relevant physiological conditions over time (24 h). 2-PAM was rapidly released from the pores of MIL-125-NH2 in vitro.
Highlights
Organophosphate (OP) compounds, such as insecticides and nerve agents, are known for their ability to inhibit acetylcholinesterase (AChE) [1] by forming a covalent bond with a serine residue in the active site of AChE
The nerve agent antidote 2-PAM was successfully encapsulated into the nano-sized MIL-125-NH2
Using Grand Canonical Monte Carlo (GCMC) calculations, the saturation was estimated for 2-PAM in MIL-125-NH2 nanoparticles
Summary
Organophosphate (OP) compounds, such as insecticides and nerve agents, are known for their ability to inhibit acetylcholinesterase (AChE) [1] by forming a covalent bond with a serine residue in the active site of AChE. Current therapeutic treatment of OP poisoning entails the administration of a mixture of atropine (to block the AChE receptor), diazepam (an anticonvulsant) and a compound generally referred to as “oxime”, which is capable of restoring the activity of AChE An example of such an oxime is pralidoxime (2-pyridinium aldoxime methyl chloride or 2-PAM; Figure 1a), which reactivates OP-inhibited AChE by attacking the covalent bond between the serine and the OP [3]. The larger particle size of the MIL-125-NH2 aqueous solution can be attributed to the aggregation of the NPs as a consequence of the almost neutrally charged surface (ζ-potential = −7 ± 4 mV; note here the influence of the initial pH, see below for further explanations), which contrasts with the higher ζ-potentials measured for ethanol or methanol (from −40 to −47 mV, respectively). OH or Tci–hOargHed psproetocnieasteadtatmhieneos u(–tNerH3s+u).rfAalctheo,utghheosneeocabnsneortveaxtciloundes tshue gpgreessent ctehoaftTit–hOeHeoxrteTri–nOaHl 2surface is mostly cospmecpieossaetdthoefooutregrasnurifcaclein, tkheesres.observations suggest that the external surface is mostly composed of organic linkers
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