期刊
ACS APPLIED MATERIALS & INTERFACES
卷 15, 期 10, 页码 12631-12642出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsami.2c18929
关键词
metal-organic framework; nerve agent; pralidoxime chloride; drug delivery; targeted treatment; preparation and characterization
It is crucial to develop a sustained-release pralidoxime chloride (2-PAM) drug system that can target the brain for the treatment of neurotoxicant poisoning. In this study, thiamine (VB1) was incorporated onto the surface of MIL-101-NH2(Fe) nanoparticles, which can bind to the thiamine transporter on the blood-brain barrier. Pralidoxime chloride was loaded within the composite, resulting in a composite drug (2-PAM@VB1-MIL-101-NH2(Fe)) with a loading capacity of 14.8% (wt). The composite drug showed a pH-dependent drug release rate, with a maximum release rate of 77.5% at pH 4. Furthermore, the composite drug exhibited sustained release and stable reactivation of poisoned acetylcholinesterase (AChE) in mice, with a reactivation rate of 42.7% in ocular blood samples at 72 h. Cross-blood-brain-barrier penetration and AChE activity restoration in the brain of poisoned mice were observed with the composite drug. It is anticipated that this composite drug can serve as a stable therapeutic option with brain targeting and prolonged drug release properties for nerve agent intoxication in the middle and late stages of treatment.
It is very important to establish a sustained-release pralidoxime chloride (2-PAM) drug system with brain targeting function for the treatment of neurotoxicant poisoning. Herein, Vitamin B1 (VB1), also known as thiamine, which can specifically bind to the thiamine transporter on the surface of the blood-brain barrier, was incorporated onto the surface of MIL-101-NH2(Fe) nanoparticles with a size of similar to 100 nm. Pralidoxime chloride was further loaded within the interior of the above resulted composite by soaking, and a resulting composite drug (denoted as 2-PAM@ VB1-MIL-101-NH2(Fe)) with a loading capacity of 14.8% (wt) was obtained. The results showed that the drug release rate of the composite drug was increased in PBS solution with the increase of pH (2-7.4) and a maximum drug release rate of 77.5% at pH 4. Experiments on the treatment of poisoning by gavage with the nerve agent sarin in mice combined with atropine revealed that sustained release of 2-PAM from the composite drug was achieved for more than 72 h. Sustained and stable reactivation of poisoned acetylcholinesterase (AChE) was observed with an enzyme reactivation rate of 42.7% in the ocular blood samples at 72 h. By using both zebrafish brain and mouse brain as models, we found that the composite drug could effectively cross the blood-brain barrier and restore the AChE activity in the brain of poisoned mice. The composite drug is expected to be a stable therapeutic drug with brain targeting and prolonged drug release properties for nerve agent intoxication in the middle and late stages of treatment.
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