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Enzyme Nanoreactor for In Vivo Detoxification of Organophosphates
ACS Applied Materials & Interfaces ( IF 8.3 ) Pub Date : 2022-04-19 , DOI: 10.1021/acsami.2c03210 Tatiana Pashirova 1 , Zukhra Shaihutdinova 1, 2 , Milana Mansurova 2 , Renata Kazakova 2 , Dinara Shambazova 2 , Andrei Bogdanov 1 , Dmitry Tatarinov 1 , David Daudé 3 , Pauline Jacquet 3 , Eric Chabrière 3, 4 , Patrick Masson 2
ACS Applied Materials & Interfaces ( IF 8.3 ) Pub Date : 2022-04-19 , DOI: 10.1021/acsami.2c03210 Tatiana Pashirova 1 , Zukhra Shaihutdinova 1, 2 , Milana Mansurova 2 , Renata Kazakova 2 , Dinara Shambazova 2 , Andrei Bogdanov 1 , Dmitry Tatarinov 1 , David Daudé 3 , Pauline Jacquet 3 , Eric Chabrière 3, 4 , Patrick Masson 2
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A nanoreactor containing an evolved mutant of Saccharolobus solfataricus phosphotriesterase (L72C/Y97F/Y99F/W263V/I280T) as a catalytic bioscavenger was made for detoxification of organophosphates. This nanoreactor intended for treatment of organophosphate poisoning was studied against paraoxon (POX). Nanoreactors were low polydispersity polymersomes containing a high concentration of enzyme (20 μM). The polyethylene glycol–polypropylene sulfide membrane allowed for penetration of POX and exit of hydrolysis products. In vitro simulations under second order conditions showed that 1 μM enzyme inactivates 5 μM POX in less than 10 s. LD50-shift experiments of POX-challenged mice through intraperitoneal (i.p.) and subcutaneous (s.c.) injections showed that intravenous administration of nanoreactors (1.6 nmol enzyme) protected against 7 × LD50i.p. in prophylaxis and 3.3 × LD50i.p. in post-exposure treatment. For mice s.c.-challenged, LD50 shifts were more pronounced: 16.6 × LD50 in prophylaxis and 9.8 × LD50 in post-exposure treatment. Rotarod tests showed that transitory impaired neuromuscular functions of challenged mice were restored the day of experiments. No deterioration was observed in the following days and weeks. The high therapeutic index provided by prophylactic administration of enzyme nanoreactors suggests that no other drugs are needed for protection against acute POX toxicity. For post-exposure treatment, co-administration of classical drugs would certainly have beneficial effects against transient incapacitation.
中文翻译：
用于有机磷酸盐体内解毒的酶纳米反应器
制备含有Saccharolobus solfataricus磷酸三酯酶 (L72C/Y97F/Y99F/W263V/I280T) 作为催化生物清除剂的进化突变体的纳米反应器，用于有机磷酸盐的解毒。这种用于治疗有机磷中毒的纳米反应器针对对氧磷 (POX) 进行了研究。纳米反应器是含有高浓度酶 (20 μM) 的低多分散性聚合体。聚乙二醇-聚丙烯硫化物膜允许 POX 的渗透和水解产物的排出。二级条件下的体外模拟表明，1 μM 酶可在 10 秒内灭活 5 μM POX。通过腹膜内（ip ）和皮下（sc ) 注射表明，静脉注射纳米反应器（1.6 nmol 酶）可防止 7 × LD 50 i.p. 在预防和 3.3 × LD 50 i.p. 在暴露后处理中。对于接受sc攻击的小鼠，LD 50变化更明显：预防性治疗中 16.6 × LD 50和 9.8 × LD 50在暴露后处理中。旋转棒测试表明，受攻击小鼠的暂时性神经肌肉功能受损在实验当天恢复。在接下来的几天和几周内没有观察到恶化。酶纳米反应器的预防性给药提供的高治疗指数表明不需要其他药物来保护免受急性 POX 毒性。对于暴露后治疗，经典药物的共同给药肯定会对暂时性失能产生有益的影响。
更新日期：2022-04-19
中文翻译：
用于有机磷酸盐体内解毒的酶纳米反应器
制备含有Saccharolobus solfataricus磷酸三酯酶 (L72C/Y97F/Y99F/W263V/I280T) 作为催化生物清除剂的进化突变体的纳米反应器，用于有机磷酸盐的解毒。这种用于治疗有机磷中毒的纳米反应器针对对氧磷 (POX) 进行了研究。纳米反应器是含有高浓度酶 (20 μM) 的低多分散性聚合体。聚乙二醇-聚丙烯硫化物膜允许 POX 的渗透和水解产物的排出。二级条件下的体外模拟表明，1 μM 酶可在 10 秒内灭活 5 μM POX。通过腹膜内（ip ）和皮下（sc ) 注射表明，静脉注射纳米反应器（1.6 nmol 酶）可防止 7 × LD 50 i.p. 在预防和 3.3 × LD 50 i.p. 在暴露后处理中。对于接受sc攻击的小鼠，LD 50变化更明显：预防性治疗中 16.6 × LD 50和 9.8 × LD 50在暴露后处理中。旋转棒测试表明，受攻击小鼠的暂时性神经肌肉功能受损在实验当天恢复。在接下来的几天和几周内没有观察到恶化。酶纳米反应器的预防性给药提供的高治疗指数表明不需要其他药物来保护免受急性 POX 毒性。对于暴露后治疗，经典药物的共同给药肯定会对暂时性失能产生有益的影响。
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