Strategies for enhanced bioavailability of oxime reactivators in the central nervous system

Prchalova, Eliska; Kohoutova, Zuzana; Knittelova, Karolina; Malinak, David; Musilek, Kamil

doi:10.1007/s00204-023-03587-0

Cited by 5 publications

(1 citation statement)

References 173 publications

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“…The creation of nanoreactors for trapping toxicants involves the complete sealing of enzyme molecules inside an nR body, and must ensure long-term circulation in the body to trap and neutralize toxicants present in the bloodstream and may be slowly released from cellular and organ depot sites, e.g., OP molecules may accumulate in fat from where they are subsequently slowly released into the bloodstream again [2,20,21]. Attempts to use OP-reacting enzymes and their encapsulated forms for stoichiometric or catalytic inactivation of OPs have been undertaken for more than 20 years and have led to very effective formulations [22,23] and novel nanoscavenger devices for OP detoxification [24,25]. However, important issues, such as the operational stability of nano-formulations and fate in organisms after administration (degradation, elimination, and immunogenicity) for the safe use of non-human enzymes have not been completely solved [26][27][28].…”

Section: Introductionmentioning

confidence: 99%

Tuning the Envelope Structure of Enzyme Nanoreactors for In Vivo Detoxification of Organophosphates

Pashirova,

Shaihutdinova,

Tatarinov

et al. 2023

IJMS

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Encapsulated phosphotriesterase nanoreactors show their efficacy in the prophylaxis and post-exposure treatment of poisoning by paraoxon. A new enzyme nanoreactor (E-nRs) containing an evolved multiple mutant (L72C/Y97F/Y99F/W263V/I280T) of Saccharolobus solfataricus phosphotriesterase (PTE) for in vivo detoxification of organophosphorous compounds (OP) was made. A comparison of nanoreactors made of three- and di-block copolymers was carried out. Two types of morphology nanoreactors made of di-block copolymers were prepared and characterized as spherical micelles and polymersomes with sizes of 40 nm and 100 nm, respectively. The polymer concentrations were varied from 0.1 to 0.5% (w/w) and enzyme concentrations were varied from 2.5 to 12.5 μM. In vivo experiments using E-nRs of diameter 106 nm, polydispersity 0.17, zeta-potential −8.3 mV, and loading capacity 15% showed that the detoxification efficacy against paraoxon was improved: the LD50 shift was 23.7xLD50 for prophylaxis and 8xLD50 for post-exposure treatment without behavioral alteration or functional physiological changes up to one month after injection. The pharmacokinetic profiles of i.v.-injected E-nRs made of three- and di-block copolymers were similar to the profiles of the injected free enzyme, suggesting partial enzyme encapsulation. Indeed, ELISA and Western blot analyses showed that animals developed an immune response against the enzyme. However, animals that received several injections did not develop iatrogenic symptoms.

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