Cation-Exchangeable Pralidoxime Chloride@bio-MOF-1 as a Treatment for Nerve Agent Poisoning and Sulfur Mustard Skin Poisoning in Animals

Abstract

A 2-PAM@bio-MOF-1 composite was prepared by cationic exchange of counter N,N-dimethylammonium cations in the pores of the anionic, biocompatible metal-organic framework (bio-MOF-1) with pralidoxime chloride (2-PAM-Cl) by impregnation. In vitro drug release measurements revealed that the release rate of 2-PAM from 2-PAM@bio-MOF-1 in simulated body fluid (SBF) was more than four-fold higher than that in deionized water, indicating that the presence of endogenous cations in SBF triggered the release of 2-PAM through cation exchange. The release of 2-PAM was rapid within the first 10 h but was much slower over the period of 10-50 h. At room temperature, the maximum release rate of 2-PAM was 88.5% (15 mg of 2-PAM@bio-MOF-1 in 1 mL of SBF), indicating that the drug was efficiently released from the composite MOF in SBF. In simulated gastric fluid, 64.3% of 2-PAM was released from bio-MOF-1 into the simulated gastric fluid after 50h. This suggested that 2-PAM@bio-MOF-1 might be effective for enabling the slow release of 2-PAM in the human body. Indeed, the maximum reactivation rate of acetylcholinesterase in sarin-poisoned mice reached 82.5%. In addition, 2-PAM@bio-MOF-1 demonstrated the ability to adsorb and remove sulfur mustard (HD) in solution and from the skin of guinea pigs.

Scheme 1. Schematic Diagram of the Synthesis of 2-PAM@bio-MOF-1 by Exchanging Me₂NH²⁺ and 2-PAM in Bio-MOF-1, as well as Sustained Release of 2-PAM Facilitated by Exchange of 2-PAM with Metal Cations in Bodily Fluids

Figure 1

FT-IR spectra of 2-PAM-Cl, bio-MOF-1, and 2-PAM@bio-MOF-1 over the spectral window of 4000–400 cm^–1 after preparing a KBr pellet of each sample.

Figure 2

Left: P-XRD spectra of (a) 2-PAM@bio-MOF-1, (b) bio-MOF, and (c) 2-PAM@bio-MOF-1 after drug release; (d) simulated P-XRD spectrum of bio-MOF-1. Right: SEM images of bio-MOF-1 (a) and 2-PAM@bio-MOF-1 after the 2-PAM release experiment (b).

Figure 3

Drug release curves of 2-PAM@bio-MOF-1 (15 mg) in SBF solution [(1 mL of SBF solution, pH = 7.4)] (black curve) (a), simulated gastric fluid [1 mL of simulated gastric fluid (PBS), pH = 1.2] (blue curve) (b), and deionized water (1 mL of deionized water) (red curve) (c) over the period of 50 h at 37 °C.

Figure 4

Comparison of the AChE activity between the mice poisoned with sarin (exposure group, black line) and the sarin-poisoned mice treated with atropine and 2-PAM@bio-MOF-1 (treatment group, red curve) over the course of 2–28 h. In the exposure group, the sarin dose was 1.1 × LD₅₀; in the treatment group, the sarin dose was 1.5 × LD₅₀, the atropine dose was 10 mg/kg, and the 2-PAM@bio-MOF-1 dose was 283.6 mg/kg.

Figure 5

Left: Comparison of the decontamination efficacy of HD-poisoned guinea pigs using activated white clay, bio-MOF-1, and 2-PAM@bio-MOF-1. The severity of the erythemas within the pre-labeled areas of the epidermis of the guinea pigs were monitored 1, 2, and 3 days after decontamination. From left to right: blank control group (A), poisoned group (B), activated clay group (C), bio-MOF-1 (D), and 2-PAM@bio-MOF-1 (E) group. Right: Skin irritation response scores (based on the extent of erythema) of the HD-poisoned guinea pigs with and without decontamination with activated white clay, bio-MOF-1, or 2-PAM@bio-MOF-1. Experimental conditions: 2 μL of HD; 1 min exposure time; 20 mg dose of activated white clay, bio-MOF-1, or 2-PAM@bio-MOF-1.