Abstract
Oxime reactivators of acetylcholinesterase are commonly used to treat highly toxic organophosphate poisoning. They are effective nucleophiles that can restore the catalytic activity of acetylcholinesterase; however, their main limitation is the difficulty in crossing the blood–brain barrier (BBB) because of their strongly hydrophilic nature. Various approaches to overcome this limitation and enhance the bioavailability of oxime reactivators in the CNS have been evaluated; these include structural modifications, conjugation with molecules that have transporters in the BBB, bypassing the BBB through intranasal delivery, and inhibition of BBB efflux transporters. A promising approach is the use of nanoparticles (NPs) as the delivery systems. Studies using mesoporous silica nanomaterials, poly (l-lysine)-graft-poly(ethylene oxide) NPs, metallic organic frameworks, poly(lactic-co-glycolic acid) NPs, human serum albumin NPs, liposomes, solid lipid NPs, and cucurbiturils, have shown promising results. Some NPs are considered as nanoreactors for organophosphate detoxification; these combine bioscavengers with encapsulated oximes. This study provides an overview and critical discussion of the strategies used to enhance the bioavailability of oxime reactivators in the central nervous system.
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Abbreviations
- ACh:
-
Acetylcholine
- AChE:
-
Acetylcholinesterase
- AD:
-
Alzheimer’s disease
- BBB:
-
Blood–brain barrier
- BChE:
-
Butyrylcholinesterase
- CAS:
-
Catalytic active site
- CBs:
-
Cucurbiturils
- ChEs:
-
Cholinesterases
- CNS:
-
Central nervous system
- CWA:
-
Chemical warfare agents
- DFP:
-
Diisopropyl fluorophosphate
- DHDHAB:
-
Dihexadecylmethylhydroxyethyl ammonium bromide
- GLUT1:
-
Glucose transporter protein type 1
- 3-HPA:
-
6-(5-(6,7-Dimethoxy-3,4-dihydroisochinolin-2(1H)-yl)pentyl)-3-hydroxypicolinaldehyde oxime
- LüH-6:
-
Obidoxime
- MILs:
-
Materials of Institut Lavoisier
- MMB-4:
-
Methoxime
- MOFs:
-
Metal organic frameworks
- MSMs:
-
Mesoporous silica materials
- MSN:
-
Mesoporous silica nanoparticles
- NA:
-
Nerve agents
- NPs:
-
Nanoparticles
- OP:
-
Organophosphate
- OPAA:
-
Organophosphorus acid anhydrolase
- 2-PAM:
-
Pralidoxime
- 4-PAM:
-
4-Pyridine aldoxime
- PAMPA:
-
Parallel artificial membrane permeability
- PAS:
-
Peripheral aromatic site
- PEG:
-
Polyethylene glycol
- P-gp:
-
P-Glycoprotein
- PLGA:
-
Poly(lactic-co-glycolic acid)
- PLL-g-PEO:
-
Poly(l-lysine)-graft-poly(ethylene oxide)
- PON-1:
-
Paraoxonase-1
- PTE:
-
Phosphotriesterase
- SLNs:
-
Solid lipid nanoparticles
- STEM:
-
Scanning transmission electron microscopy
- TEPP:
-
Tetraethyl pyrophosphate
- TMB-4:
-
Trimedoxime
References
Agrawal M, Saraf S, Saraf S et al (2020) Recent strategies and advances in the fabrication of nano lipid carriers and their application towards brain targeting. J Control Release 321:372–415. https://doi.org/10.1016/j.jconrel.2020.02.020
Albuquerque EX, Pereira EFR, Aracava Y et al (2006) Effective countermeasure against poisoning by organophosphorus insecticides and nerve agents. PNAS 103:13220–13225. https://doi.org/10.1073/pnas.0605370103
Alexis F, Pridgen E, Molnar LK, Farokhzad OC (2008) Factors affecting the clearance and biodistribution of polymeric nanoparticles. Mol Pharm 5:505–515. https://doi.org/10.1021/mp800051m
Almáši M, Zeleňák V, Gyepes R et al (2020) A series of four novel alkaline earth metal–organic frameworks constructed of Ca( ii ), Sr( ii ), Ba( ii ) ions and tetrahedral MTB linker: structural diversity, stability study and low/high-pressure gas adsorption properties. RSC Adv 10:32323–32334. https://doi.org/10.1039/D0RA05145D
Amin MdL (2013) P-glycoprotein Inhibition for optimal drug delivery. Drug Target Insights 7:27–34. https://doi.org/10.4137/DTI.S12519
Andrýs R, Klusoňová A, Lísa M, Karasová JŽ (2020) Encapsulation of oxime acetylcholinesterase reactivators: influence of physiological conditions on the stability of oxime-cucurbit[7]uril complexes. New J Chem 44:14367–14372. https://doi.org/10.1039/D0NJ03102J
Andrýs R, Klusoňová A, Lísa M et al (2021) Effect of oxime encapsulation on acetylcholinesterase reactivation: pharmacokinetic study of the asoxime–cucurbit[7]uril complex in mice using hydrophilic interaction liquid chromatography-mass spectrometry. Mol Pharm 18:2416–2427. https://doi.org/10.1021/acs.molpharmaceut.1c00257
Antonijevic B, Stojiljkovic MP (2007) Unequal efficacy of pyridinium oximes in acute organophosphate poisoning. Clin Med Res 5:71–82. https://doi.org/10.3121/cmr.2007.701
Arnott JA, Planey SL (2012) The influence of lipophilicity in drug discovery and design. Expert Opin Drug Discov 7:863–875. https://doi.org/10.1517/17460441.2012.714363
Ashani Y, Bhattacharjee AK, Leader H et al (2003) Inhibition of cholinesterases with cationic phosphonyl oximes highlights distinctive properties of the charged pyridine groups of quaternary oxime reactivators. Biochem Pharmacol 66:191–202. https://doi.org/10.1016/s0006-2952(03)00204-1
Atanasov VN, Petrova I, Dishovsky C (2013) In vitro investigation of efficacy of new reactivators on OPC inhibited rat brain acetylcholinesterase. Chem Biol Interact 203:139–143. https://doi.org/10.1016/j.cbi.2012.11.020
Bajgar J (2004) Organophosphates/nerve agent poisoning: mechanism of action, diagnosis, prophylaxis, and treatment. Advances in clinical chemistry. Elsevier, pp 151–216
Bajgar J, Fusek J, Kuca K et al (2007) Treatment of organophosphate intoxication using cholinesterase reactivators: facts and fiction. Mini Rev Med Chem 7:461–466. https://doi.org/10.2174/138955707780619581
Barjasteh M, Vossoughi M, Bagherzadeh M, Bagheri KP (2022) Green synthesis of PEG-coated MIL-100(Fe) for controlled release of dacarbazine and its anticancer potential against human melanoma cells. Int J Pharm 618:121647. https://doi.org/10.1016/j.ijpharm.2022.121647
Becker C, Worek F, John H (2010) Chromatographic analysis of toxic phosphylated oximes (POX): a brief overview. Drug Test Anal 2:460–468. https://doi.org/10.1002/dta.167
Bester SM, Guelta MA, Cheung J et al (2018) Structural insights of stereospecific inhibition of human acetylcholinesterase by VX and subsequent reactivation by HI-6. Chem Res Toxicol 31:1405–1417. https://doi.org/10.1021/acs.chemrestox.8b00294
Bhonsle JB, Causey R, Oyler BL et al (2013) Evaluation and computational characterization of the facilitated transport of Glc carbon C-1 oxime reactivators across a blood brain barrier model. Chem Biol Interact 203:129–134. https://doi.org/10.1016/j.cbi.2012.09.012
Brambilla D, Le Droumaguet B, Nicolas J et al (2011) Nanotechnologies for Alzheimer’s disease: diagnosis, therapy, and safety issues. Nanomedicine 7:521–540. https://doi.org/10.1016/j.nano.2011.03.008
Buzyurova DN, Pashirova TN, Zueva IV et al (2020) Surface modification of pralidoxime chloride-loaded solid lipid nanoparticles for enhanced brain reactivation of organophosphorus-inhibited AChE: pharmacokinetics in rat. Toxicology 444:152578. https://doi.org/10.1016/j.tox.2020.152578
Chatzikleanthous D, O’Hagan DT, Adamo R (2021) Lipid-based nanoparticles for delivery of vaccine adjuvants and antigens: toward multicomponent vaccines. Mol Pharm 18:2867–2888. https://doi.org/10.1021/acs.molpharmaceut.1c00447
Chen X, Tong R, Shi Z et al (2018) MOF nanoparticles with encapsulated autophagy inhibitor in controlled drug delivery system for antitumor. ACS Appl Mater Interfaces 10:2328–2337. https://doi.org/10.1021/acsami.7b16522
Chigumira W, Maposa P, Gadaga LL et al (2015) Preparation and evaluation of pralidoxime-loaded PLGA nanoparticles as potential carriers of the drug across the blood brain barrier. J Nanomater 2015:e692672. https://doi.org/10.1155/2015/692672
Choi YH, Liu F, Kim JS et al (1998) Polyethylene glycol-grafted poly-l-lysine as polymeric gene carrier. J Control Release 54:39–48. https://doi.org/10.1016/s0168-3659(97)00174-0
Da Silva O, Probst N, Landry C et al (2022) A new class of Bi- and trifunctional sugar oximes as antidotes against organophosphorus poisoning. J Med Chem 65:4649–4666. https://doi.org/10.1021/acs.jmedchem.1c01748
Dadparvar M, Wagner S, Wien S et al (2011) HI 6 human serum albumin nanoparticles–development and transport over an in vitro blood-brain barrier model. Toxicol Lett 206:60–66. https://doi.org/10.1016/j.toxlet.2011.06.027
Dadparvar M, Wagner S, Wien S et al (2014) Freeze-drying of HI-6-loaded recombinant human serum albumin nanoparticles for improved storage stability. Eur J Pharm Biopharm 88:510–517. https://doi.org/10.1016/j.ejpb.2014.06.008
Dail MB, Meek EC, Chambers HW, Chambers JE (2019) In vitro P-glycoprotein activity does not completely explain in vivo efficacy of novel centrally effective oxime acetylcholinesterase reactivators. Drug Chem Toxicol 42:403–408. https://doi.org/10.1080/01480545.2018.1461902
Daraee H, Etemadi A, Kouhi M et al (2016) Application of liposomes in medicine and drug delivery. Artif Cells Nanomed Biotechnol 44:381–391. https://doi.org/10.3109/21691401.2014.953633
Dong J-H, Ma Y, Li R et al (2021) Smart MSN-drug-delivery system for tumor cell targeting and tumor microenvironment release. ACS Appl Mater Interfaces 13:42522–42532. https://doi.org/10.1021/acsami.1c14189
Dreis S, Rothweiler F, Michaelis M et al (2007) Preparation, characterisation and maintenance of drug efficacy of doxorubicin-loaded human serum albumin (HSA) nanoparticles. Int J Pharm 341:207–214. https://doi.org/10.1016/j.ijpharm.2007.03.036
Ellman GL, Courtney KD, Andres V, Feather-Stone RM (1961) A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol 7:88–95. https://doi.org/10.1016/0006-2952(61)90145-9
Estevez J, Vilanova E (2009) Model equations for the kinetics of covalent irreversible enzyme inhibition and spontaneous reactivation: esterases and organophosphorus compounds. Crit Rev Toxicol 39:427–448. https://doi.org/10.1080/10408440802412309
Evans OR, Xiong R-G, Wang Z et al (1999) Crystal engineering of acentric diamondoid metal-organic coordination networks. Angew Chem Int Ed Engl 38:536–538. https://doi.org/10.1002/(SICI)1521-3773(19990215)38:4%3c536::AID-ANIE536%3e3.0.CO;2-3
Eyer P, Hell W, Kawan A, Klehr H (1986) Studies on the decomposition of the oxime HI 6 in aqueous solution. Arch Toxicol 59:266–271. https://doi.org/10.1007/BF00290549
Eyer P, Hagedorn I, Ladstetter B (1988) Study on the stability of the oxime HI 6 in aqueous solution. Arch Toxicol 62:224–226. https://doi.org/10.1007/BF00570145
Fan N, Li Q, Liu Y et al (2023) Preparation of an HI-6-loaded brain-targeted liposomes based on the nasal delivery route and the evaluation of its reactivation of central toxic acetylcholinesterase. Eur J Pharm Sci. https://doi.org/10.1016/j.ejps.2023.106406
Fundarò A, Cavalli R, Bargoni A et al (2000) Non-stealth and stealth solid lipid nanoparticles (SLN) carrying doxorubicin: pharmacokinetics and tissue distribution after i.v. administration to rats. Pharmacol Res 42:337–343. https://doi.org/10.1006/phrs.2000.0695
Gänger S, Schindowski K (2018) Tailoring formulations for intranasal nose-to-brain delivery: a review on architecture, physico-chemical characteristics and mucociliary clearance of the nasal olfactory mucosa. Pharmaceutics 10:E116. https://doi.org/10.3390/pharmaceutics10030116
Gao H, Pang Z, Jiang X (2013) Targeted delivery of nano-therapeutics for major disorders of the central nervous system. Pharm Res 30:2485–2498. https://doi.org/10.1007/s11095-013-1122-4
Garcia GE, Campbell AJ, Olson J et al (2010) Novel oximes as blood-brain barrier penetrating cholinesterase reactivators. Chem-Biol Interact 187:199–206. https://doi.org/10.1016/j.cbi.2010.02.033
Gastaldi L, Battaglia L, Peira E et al (2014) Solid lipid nanoparticles as vehicles of drugs to the brain: current state of the art. Eur J Pharm Biopharm 87:433–444. https://doi.org/10.1016/j.ejpb.2014.05.004
Gaydess A, Duysen E, Li Y et al (2010) Visualization of exogenous delivery of nanoformulated butyrylcholinesterase to the central nervous system. Chem Biol Interact 187:295–298. https://doi.org/10.1016/j.cbi.2010.01.005
Gentile P, Chiono V, Carmagnola I, Hatton PV (2014) An overview of poly(lactic-co-glycolic) acid (PLGA)-based biomaterials for bone tissue engineering. Int J Mol Sci 15:3640–3659. https://doi.org/10.3390/ijms15033640
Ghitman J, Biru EI, Stan R, Iovu H (2020) Review of hybrid PLGA nanoparticles: future of smart drug delivery and theranostics medicine. Mater Des 193:108805. https://doi.org/10.1016/j.matdes.2020.108805
Giri S, Trewyn BG, Stellmaker MP, Lin VS-Y (2005) Stimuli-responsive controlled-release delivery system based on mesoporous silica nanorods capped with magnetic nanoparticles. Angew Chem Int Ed Engl 44:5038–5044. https://doi.org/10.1002/anie.200501819
Gorecki L, Korabecny J, Musilek K et al (2016) SAR study to find optimal cholinesterase reactivator against organophosphorous nerve agents and pesticides. Arch Toxicol 90:2831–2859. https://doi.org/10.1007/s00204-016-1827-3
Gorecki L, Korabecny J, Musilek K et al (2017) Progress in acetylcholinesterase reactivators and in the treatment of organophosphorus intoxication: a patent review (2006–2016). Expert Opin Ther Patents 27:971–985. https://doi.org/10.1080/13543776.2017.1338275
Gorecki L, Hepnarova V, Karasova JZ et al (2021) Development of versatile and potent monoquaternary reactivators of acetylcholinesterase. Arch Toxicol 95:985–1001. https://doi.org/10.1007/s00204-021-02981-w
Handl J, Malinak D, Capek J et al (2021) Effects of charged oxime reactivators on the HK-2 cell line in renal toxicity screening. Chem Res Toxicol 34:699–703. https://doi.org/10.1021/acs.chemrestox.0c00489
Hanson LR, Frey WH (2008) Intranasal delivery bypasses the blood-brain barrier to target therapeutic agents to the central nervous system and treat neurodegenerative disease. BMC Neurosci 9:S5. https://doi.org/10.1186/1471-2202-9-S3-S5
Hartlieb KJ, Ferris DP, Holcroft JM et al (2017) Encapsulation of ibuprofen in CD-MOF and related bioavailability studies. Mol Pharm 14:1831–1839. https://doi.org/10.1021/acs.molpharmaceut.7b00168
Heldman E, Ashani Y, Raveh L, Rachaman ES (1986) Sugar conjugates of pyridinium aldoximes as antidotes against organophosphate poisoning. Carbohyd Res 151:337–347. https://doi.org/10.1016/S0008-6215(00)90353-7
Hervé F, Ghinea N, Scherrmann J-M (2008) CNS Delivery Via Adsorptive Transcytosis. The AAPS Journal 10:455–472. https://doi.org/10.1208/s12248-008-9055-2
Hoyos-Ceballos GP, Ruozi B, Ottonelli I et al (2020) PLGA-PEG-ANG-2 nanoparticles for blood-brain barrier crossing: proof-of-concept study. Pharmaceutics 12:E72. https://doi.org/10.3390/pharmaceutics12010072
Huxford RC, Della Rocca J, Lin W (2010) Metal–organic frameworks as potential drug carriers. Curr Opin Chem Biol 14:262–268. https://doi.org/10.1016/j.cbpa.2009.12.012
Jain KK (2012) Nanobiotechnology-based strategies for crossing the blood-brain barrier. Nanomedicine (lond) 7:1225–1233. https://doi.org/10.2217/nnm.12.86
Jeong HC, Kang NS, Park N-J et al (2009) Reactivation potency of fluorinated pyridinium oximes for acetylcholinesterases inhibited by paraoxon organophosphorus agent. Bioorg Med Chem Lett 19:1214–1217. https://doi.org/10.1016/j.bmcl.2008.12.070
Jett DA, Spriggs SM (2020) Translational research on chemical nerve agents. Neurobiol Dis 133:104335. https://doi.org/10.1016/j.nbd.2018.11.020
Jokanović M (2012) Structure-activity relationship and efficacy of pyridinium oximes in the treatment of poisoning with organophosphorus compounds: a review of recent data. Curr Top Med Chem 12:1775–1789
Joosen M, van der Schans M, van Dijk C et al (2011) Increasing oxime efficacy by blood-brain barrier modulation. Toxicol Lett 206:67–71. https://doi.org/10.1016/j.toxlet.2011.05.231
Karasova J, Petr S, Kuca K (2010) In vitro screening of blood-brain barrier penetration of clinically used acetylcholinesterase reactivators. J Appl Biomed 10:35–40. https://doi.org/10.2478/v10136-009-0005-9
Karasova JZ, Zemek F, Bajgar J et al (2011) Partition of bispyridinium oximes (trimedoxime and K074) administered in therapeutic doses into different parts of the rat brain. J Pharm Biomed Anal 54:1082–1087. https://doi.org/10.1016/j.jpba.2010.11.024
Karasova JZ, Chladek J, Hroch M et al (2013) Pharmacokinetic study of two acetylcholinesterase reactivators, trimedoxime and newly synthesized oxime K027, in rat plasma: pharmacokinetic study of oxime K027 and trimedoxime. J Appl Toxicol 33:18–23. https://doi.org/10.1002/jat.1699
Kassa J, Karasova JZ, Caisberger F et al (2010a) A comparison of reactivating and therapeutic efficacy of the oxime K203 and its fluorinated analog (KR-22836) with currently available oximes (obidoxime, trimedoxime, HI-6) against tabun in rats and mice. J Enzyme Inhib Med Chem 25:480–484. https://doi.org/10.3109/14756360903257918
Kassa J, Karasova JZ, Tesarova S et al (2010b) A comparison of neuroprotective efficacy of the oxime K203 and its fluorinated analogue (KR-22836) with obidoxime in tabun-poisoned rats. Basic Clin Pharmacol Toxicol 107:861–867. https://doi.org/10.1111/j.1742-7843.2010.00588.x
Kilianova Z, Ciznarova N, Szmicsekova K et al (2020) Expression of cholinesterases and their anchoring proteins in rat heart. Can J Physiol Pharmacol 98:473–476. https://doi.org/10.1139/cjpp-2019-0565
Kim S-N, Kim J, Kim H-Y et al (2013) Adsorption/catalytic properties of MIL-125 and NH2–MIL-125. Catal Today 204:85–93. https://doi.org/10.1016/j.cattod.2012.08.014
Kitagawa S, Kitaura R, Noro S (2004) Functional porous coordination polymers. Angew Chem Int Ed 43:2334–2375. https://doi.org/10.1002/anie.200300610
Kobrlova T, Soukup O (2020) Effect of P-glycoprotein on the availability of oxime reactivators in the brain. Toxicology 443:152541. https://doi.org/10.1016/j.tox.2020.152541
Kobrlova T, Korabecny J, Soukup O (2019) Current approaches to enhancing oxime reactivator delivery into the brain. Toxicology 423:75–83. https://doi.org/10.1016/j.tox.2019.05.006
Kresge CT, Leonowicz ME, Roth WJ et al (1992) Ordered mesoporous molecular sieves synthesized by a liquid-crystal template mechanism. Nature 359:710–712. https://doi.org/10.1038/359710a0
Krishnan JKS, Arun P, Appu AP et al (2016) Intranasal delivery of obidoxime to the brain prevents mortality and CNS damage from organophosphate poisoning. Neurotoxicology 53:64–73. https://doi.org/10.1016/j.neuro.2015.12.020
Kuca K, Jun D, Musilek K (2006) Structural requirements of acetylcholinesterase reactivators. Mini-Rev Med Chem 6:269–277
Kuca K, Musilova L, Palecek J et al (2009) Novel bisquaternary oximes—reactivation of acetylcholinesterase and butyrylcholinesterase inhibited by paraoxon. Molecules 14:4915–4921. https://doi.org/10.3390/molecules14124915
Kufleitner J, Wagner S, Worek F et al (2010) Adsorption of obidoxime onto human serum albumin nanoparticles: drug loading, particle size and drug release. J Microencapsul 27:506–513. https://doi.org/10.3109/02652041003681406
Kumar S, Malik MM, Purohit R (2017) Synthesis methods of mesoporous silica materials. Mater Today: Proc 4:350–357. https://doi.org/10.1016/j.matpr.2017.01.032
Kuznetsova DA, Gaynanova GA, Vasilieva EA et al (2022) Oxime therapy for brain AChE reactivation and neuroprotection after organophosphate poisoning. Pharmaceutics 14:1950. https://doi.org/10.3390/pharmaceutics14091950
Lagona J, Mukhopadhyay P, Chakrabarti S, Isaacs L (2005) The cucurbit[n]uril family. Angew Chem Int Ed 44:4844–4870. https://doi.org/10.1002/anie.200460675
Li H, Eddaoudi M, O’Keeffe M, Yaghi OM (1999) Design and synthesis of an exceptionally stable and highly porous metal-organic framework. Nature 402:276–279. https://doi.org/10.1038/46248
Li P, Moon S-Y, Guelta MA et al (2016) Nanosizing a metal-organic framework enzyme carrier for accelerating nerve agent hydrolysis. ACS Nano 10:9174–9182. https://doi.org/10.1021/acsnano.6b04996
Li Z, Wang C, Chen J et al (2021) uPAR targeted phototheranostic metal-organic framework nanoprobes for MR/NIR-II imaging-guided therapy and surgical resection of glioblastoma. Mater Des 198:109386. https://doi.org/10.1016/j.matdes.2020.109386
Liang YQ, Tang XC (2004) Comparative effects of huperzine A, donepezil and rivastigmine on cortical acetylcholine level and acetylcholinesterase activity in rats. Neurosci Lett 361:56–59. https://doi.org/10.1016/j.neulet.2003.12.071
Lin Y-S, Haynes CL (2010) Impacts of mesoporous silica nanoparticle size, pore ordering, and pore integrity on hemolytic activity. J Am Chem Soc 132:4834–4842. https://doi.org/10.1021/ja910846q
Locatelli E, Comes Franchini M (2012) Biodegradable PLGA-b-PEG polymeric nanoparticles: synthesis, properties, and nanomedical applications as drug delivery system. J Nanopart Res 14:1316. https://doi.org/10.1007/s11051-012-1316-4
Lockridge O (2015) Review of human butyrylcholinesterase structure, function, genetic variants, history of use in the clinic, and potential therapeutic uses. Pharmacol Ther 148:34–46. https://doi.org/10.1016/j.pharmthera.2014.11.011
Lorke DE, Kalasz H, Petroianu GA, Tekes K (2008) Entry of oximes into the brain: a review. Curr Med Chem 15:743–753. https://doi.org/10.2174/092986708783955563
Lu J, Liong M, Li Z et al (2010) Biocompatibility, biodistribution, and drug-delivery efficiency of mesoporous silica nanoparticles for cancer therapy in animals. Small 6:1794–1805. https://doi.org/10.1002/smll.201000538
Lunt J (1998) Large-scale production, properties and commercial applications of polylactic acid polymers. Polym Degrad Stab 59:145–152. https://doi.org/10.1016/S0141-3910(97)00148-1
Lushington GH, Guo J-X, Hurley MM (2006) Acetylcholinesterase: molecular modeling with the whole toolkit. Curr Top Med Chem 6:57–73. https://doi.org/10.2174/156802606775193293
Maček Hrvat N, Zorbaz T, Šinko G, Kovarik Z (2018) The estimation of oxime efficiency is affected by the experimental design of phosphylated acetylcholinesterase reactivation. Toxicol Lett 293:222–228. https://doi.org/10.1016/j.toxlet.2017.11.022
Manzano M, Vallet-Regí M (2018) Mesoporous silica nanoparticles in nanomedicine applications. J Mater Sci: Mater Med 29:65. https://doi.org/10.1007/s10856-018-6069-x
Marrs TC (2004) The role of diazepam in the treatment of nerve agent poisoning in a civilian population. Toxicol Rev 23:145–157. https://doi.org/10.2165/00139709-200423030-00002
Martínez-Carmona M, Lozano D, Baeza A et al (2017) A novel visible light responsive nanosystem for cancer treatment. Nanoscale 9:15967–15973. https://doi.org/10.1039/C7NR05050J
Masson P, Lockridge O (2010) Butyrylcholinesterase for protection from organophosphorus poisons; catalytic complexities and hysteretic behavior. Arch Biochem Biophys 494:107. https://doi.org/10.1016/j.abb.2009.12.005
Masson E, Ling X, Joseph R et al (2012) Cucurbituril chemistry: a tale of supramolecular success. RSC Adv 2:1213–1247. https://doi.org/10.1039/C1RA00768H
Maurice T, Strehaiano M, Siméon N et al (2016) Learning performances and vulnerability to amyloid toxicity in the butyrylcholinesterase knockout mouse. Behav Brain Res 296:351–360. https://doi.org/10.1016/j.bbr.2015.08.026
McGuinn WD, Cannon EP, Chui CT et al (1993) The encapsulation of squid diisopropylphosphorofluoridate-hydrolyzing enzyme within mouse erythrocytes. Fundam Appl Toxicol 21:38–43. https://doi.org/10.1006/faat.1993.1069
McKinlay AC, Xiao B, Wragg DS et al (2008) Exceptional behavior over the whole adsorption−storage−delivery cycle for NO in porous metal organic frameworks. J Am Chem Soc 130:10440–10444. https://doi.org/10.1021/ja801997r
Meng H, Mai WX, Zhang H et al (2013) Co-delivery of an optimal drug/siRNA combination using mesoporous silica nanoparticle to overcome drug resistance in breast cancer in vitro and in vivo. ACS Nano 7:994–1005. https://doi.org/10.1021/nn3044066
Mercey G, Verdelet T, Saint-André G et al (2011) First efficient uncharged reactivators for the dephosphylation of poisoned human acetylcholinesterase. Chem Commun (camb) 47:5295–5297. https://doi.org/10.1039/c1cc10787a
Mercey G, Verdelet T, Renou J et al (2012) Reactivators of acetylcholinesterase inhibited by organophosphorus nerve agents. Acc Chem Res 45:756–766. https://doi.org/10.1021/ar2002864
Mondloch JE, Katz MJ, Isley WC et al (2015) Destruction of chemical warfare agents using metal-organic frameworks. Nat Mater 14:512–516. https://doi.org/10.1038/nmat4238
Mostaghaci B, Hanifi A, Loretz B, Lehr C-M (2011) Nano-particulate calcium phosphate as a gene delivery system. InTech
Mura S, Nicolas J, Couvreur P (2013) Stimuli-responsive nanocarriers for drug delivery. Nat Mater 12:991–1003. https://doi.org/10.1038/nmat3776
Ohta H, Ohmori T, Suzuki S et al (2006) New safe method for preparation of sarin-exposed human erythrocytes acetylcholinesterase using non-toxic and stable sarin analogue isopropyl p-nitrophenyl methylphosphonate and its application to evaluation of nerve agent antidotes. Pharm Res 23:2827–2833. https://doi.org/10.1007/s11095-006-9123-1
Okuno S, Sakurada K, Ohta H et al (2008) Blood–brain barrier penetration of novel pyridinealdoxime methiodide (PAM)-type oximes examined by brain microdialysis with LC-MS/MS. Toxicol Appl Pharmacol 227:8–15. https://doi.org/10.1016/j.taap.2007.09.021
Paris JL, Cabañas MV, Manzano M, Vallet-Regí M (2015) Polymer-grafted mesoporous silica nanoparticles as ultrasound-responsive drug carriers. ACS Nano 9:11023–11033. https://doi.org/10.1021/acsnano.5b04378
Pashirova TN, Zueva IV, Petrov KA et al (2017) Nanoparticle-delivered 2-PAM for rat brain protection against paraoxon central toxicity. ACS Appl Mater Interfaces 9:16922–16932. https://doi.org/10.1021/acsami.7b04163
Pashirova TN, Braïki A, Zueva IV et al (2018a) Combination delivery of two oxime-loaded lipid nanoparticles: time-dependent additive action for prolonged rat brain protection. J Control Release 290:102–111. https://doi.org/10.1016/j.jconrel.2018.10.010
Pashirova TN, Zueva IV, Petrov KA et al (2018b) Mixed cationic liposomes for brain delivery of drugs by the intranasal route: the acetylcholinesterase reactivator 2-PAM as encapsulated drug model. Colloids Surf B Biointerfaces 171:358–367. https://doi.org/10.1016/j.colsurfb.2018.07.049
Pashirova TN, Bogdanov A, Masson P (2021) Therapeutic nanoreactors for detoxification of xenobiotics: concepts, challenges and biotechnological trends with special emphasis to organophosphate bioscavenging. Chem Biol Interact 346:109577. https://doi.org/10.1016/j.cbi.2021.109577
Pastorino F, Brignole C, Di Paolo D et al (2019) Overcoming biological barriers in neuroblastoma therapy: the vascular targeting approach with liposomal drug nanocarriers. Small. https://doi.org/10.1002/smll.201804591
Pei L, Omburo G, Mcguinn WD et al (1994) Encapsulation of phosphotriesterase within murine erythrocytes. Toxicol Appl Pharmacol 124:296–301. https://doi.org/10.1006/taap.1994.1035
Petrikovics I, Hong K, Omburo G et al (1999) Antagonism of paraoxon intoxication by recombinant phosphotriesterase encapsulated within sterically stabilized liposomes. Toxicol Appl Pharmacol 156:56–63. https://doi.org/10.1006/taap.1998.8620
Petrikovics I, Wales M, Budai M et al (2012) Nano-intercalated organophosphorus-hydrolyzing enzymes in organophosphorus antagonism. AAPS PharmSciTech 13:112–117. https://doi.org/10.1208/s12249-011-9728-5
Pulkrabkova L, Svobodova B, Konecny J et al (2023) Neurotoxicity evoked by organophosphates and available countermeasures. Arch Toxicol 97:39–72. https://doi.org/10.1007/s00204-022-03397-w
Qu M, Lin Q, He S et al (2018) A brain targeting functionalized liposomes of the dopamine derivative N-3,4-bis(pivaloyloxy)-dopamine for treatment of Parkinson’s disease. J Control Release 277:173–182. https://doi.org/10.1016/j.jconrel.2018.03.019
Rachaman ES, Ashani Y, Leader H et al (1979) Sugar-oximes, new potential antidotes against organophosphorus poisoning. Arzneimittelforschung 29:875–876. https://doi.org/10.1002/chin.197938312
Radu DR, Lai C-Y, Jeftinija K et al (2004) A polyamidoamine dendrimer-capped mesoporous silica nanosphere-based gene transfection reagent. J Am Chem Soc 126:13216–13217. https://doi.org/10.1021/ja046275m
Rastegari E, Hsiao Y-J, Lai W-Y et al (2021) An update on mesoporous silica nanoparticle applications in nanomedicine. Pharmaceutics 13:1067. https://doi.org/10.3390/pharmaceutics13071067
Rochu D, Chabrière E, Masson P (2007) Human paraoxonase: a promising approach for pre-treatment and therapy of organophosphorus poisoning. Toxicology 233:47–59. https://doi.org/10.1016/j.tox.2006.08.037
Rosenberg YJ, Mao L, Jiang X et al (2017) Post-exposure treatment with the oxime RS194B rapidly reverses early and advanced symptoms in macaques exposed to sarin vapor. Chem Biol Interact 274:50–57. https://doi.org/10.1016/j.cbi.2017.07.003
Rosenberg YJ, Wang J, Ooms T et al (2018) Post-exposure treatment with the oxime RS194B rapidly reactivates and reverses advanced symptoms of lethal inhaled paraoxon in macaques. Arch Toxicol 293:229–234. https://doi.org/10.1016/j.toxlet.2017.10.025
Sakurada K, Ohta H (2020) No promising antidote 25 years after the Tokyo subway sarin attack: a review. Legal Med 47:101761. https://doi.org/10.1016/j.legalmed.2020.101761
Sakurada K, Matsubara K, Shimizu K, et al (2003) Pralidoxime iodide (2-PAM) penetrates across the blood–brain barrier. Neurochem Res 28:1401–1407. https://doi.org/10.1023/A:1024960819430
Sánchez-López E, Espina M, Doktorovova S et al (2017) Lipid nanoparticles (SLN, NLC): overcoming the anatomical and physiological barriers of the eye—part II—ocular drug-loaded lipid nanoparticles. Eur J Pharm Biopharm 110:58–69. https://doi.org/10.1016/j.ejpb.2016.10.013
Schinkel (1999) P-Glycoprotein, a gatekeeper in the blood-brain barrier. Adv Drug Deliv Rev 36:179–194. https://doi.org/10.1016/s0169-409x(98)00085-4
Seyfoddin A, Shaw J, Al-Kassas R (2010) Solid lipid nanoparticles for ocular drug delivery. Drug Deliv 17:467–489. https://doi.org/10.3109/10717544.2010.483257
Sharom FJ (2011) The P-glycoprotein multidrug transporter. Essays Biochem 50:161–178. https://doi.org/10.1042/bse0500161
Shen L, Zhang Y, Cai Q et al (2023) HI-6-loaded PEGylated liposomes: an on-site first-aid strategy for acute organophosphorus agent poisoning. Drug Deliv 30:20–27. https://doi.org/10.1080/10717544.2022.2152132
Shi Z, Zhou Y, Fan T et al (2020) Inorganic nano-carriers based smart drug delivery systems for tumor therapy. Smart Mater Med 1:32–47. https://doi.org/10.1016/j.smaim.2020.05.002
Soukup O, Korabecny J, Malinak D et al (2018) In vitro and in silico evaluation of non-quaternary reactivators of AChE as antidotes of organophosphorus poisoning—a new hope or a blind alley? Med Chem 14:281–292. https://doi.org/10.2174/1573406414666180112105657
Stephanopoulos N, Tong GJ, Hsiao SC, Francis MB (2010) Dual-surface modified virus capsids for targeted delivery of photodynamic agents to cancer cells. ACS Nano 4:6014–6020. https://doi.org/10.1021/nn1014769
Szilasi M, Budai M, Budai L, Petrikovics I (2012) Nanoencapsulated and microencapsulated enzymes in drug antidotal therapy. Toxicol Ind Health 28:522–531. https://doi.org/10.1177/0748233711416946
Tan SY, Ang CY, Zhao Y (2017) 5.17—Smart therapeutics achieved via host-guest assemblies. In: Atwood JL (ed) Comprehensive supramolecular chemistry II. Elsevier, Oxford, pp 391–420
Terrier F, Rodriguez-Dafonte P, Guével EL, Moutiers G (2006) Revisiting the reactivity of oximate α-nucleophiles with electrophilic phosphorus centers. Relevance to detoxification of sarin, soman and DFP under mild conditions. Org Biomol Chem 4:4352–4363. https://doi.org/10.1039/B609658C
Tesarova B, Musilek K, Rex S, Heger Z (2020) Taking advantage of cellular uptake of ferritin nanocages for targeted drug delivery. J Control Release 325:176–190. https://doi.org/10.1016/j.jconrel.2020.06.026
Thiermann H, Zilker T, Eyer F et al (2009) Monitoring of neuromuscular transmission in organophosphate pesticide-poisoned patients. Toxicol Lett 191:297–304. https://doi.org/10.1016/j.toxlet.2009.09.013
Thompson CM, Gerdes JM, VanBrocklin HF (2020) Positron emission tomography studies of organophosphate chemical threats and oxime countermeasures. Neurobiol Dis 133:104455. https://doi.org/10.1016/j.nbd.2019.04.011
Topczewski JJ, Quinn DM (2013) Kinetic assessment of N-methyl-2-methoxypyridinium species as phosphonate anion methylating agents. Org Lett 15:1084–1087. https://doi.org/10.1021/ol400054m
Tougu V (2001) Acetylcholinesterase: mechanism of catalysis and inhibition. Curr Med Chem Central Nerv Syst Agents 1:155–170
Vallet-Regí M (2006) Ordered mesoporous materials in the context of drug delivery systems and bone tissue engineering. Chemistry: A Eur J 12:5934–5943. https://doi.org/10.1002/chem.200600226
Vallet-Regi M, Rámila A, del Real RP, Pérez-Pariente J (2001) A new property of MCM-41: drug delivery system. Chem Mater 13:308–311. https://doi.org/10.1021/cm0011559
Vilela SMF, Salcedo-Abraira P, Colinet I et al (2017) Nanometric MIL-125–NH2 metal–organic framework as a potential nerve agent antidote carrier. Nanomaterials (basel) 7:321. https://doi.org/10.3390/nano7100321
Wagner S, Kufleitner J, Zensi A et al (2010) Nanoparticulate transport of oximes over an in vitro blood–brain barrier model. PLoS ONE 5:e14213. https://doi.org/10.1371/journal.pone.0014213
Wang M, Thanou M (2010) Targeting nanoparticles to cancer. Pharmacol Res 62:90–99. https://doi.org/10.1016/j.phrs.2010.03.005
Wang L, Li L, Fan Y, Wang H (2013) Host-guest supramolecular nanosystems for cancer diagnostics and therapeutics. Adv Mater 25:3888–3898. https://doi.org/10.1002/adma.201301202
Wang M, Zhou C, Chen J et al (2015) Multifunctional biocompatible and biodegradable folic acid conjugated poly(ε-caprolactone)–polypeptide copolymer vesicles with excellent antibacterial activities. Bioconjugate Chem 26:725–734. https://doi.org/10.1021/acs.bioconjchem.5b00061
Wang W et al (2016) Nanoscale metal-organic framework-hemoglobin conjugates. Chem, Asian J. https://doi.org/10.1002/asia.201501216
Watson A, Opresko D, Young RA et al (2015) Chapter 9—Organophosphate nerve agents. In: Gupta RC (ed) Handbook of toxicology of chemical warfare agents, 2nd edn. Academic Press, Boston, pp 87–109
Winter M, Wille T, Musilek K et al (2016) Investigation of the reactivation kinetics of a large series of bispyridinium oximes with organophosphate-inhibited human acetylcholinesterase. Toxicol Lett 244:136–142. https://doi.org/10.1016/j.toxlet.2015.07.007
Worek F, Thiermann H (2013) The value of novel oximes for treatment of poisoning by organophosphorus compounds. Pharmacol Ther 139:249–259. https://doi.org/10.1016/j.pharmthera.2013.04.009
Worek F, Szinicz L, Eyer P, Thiermann H (2005) Evaluation of oxime efficacy in nerve agent poisoning: development of a kinetic-based dynamic model. Toxicol Appl Pharmacol 209:193–202. https://doi.org/10.1016/j.taap.2005.04.006
Worek F, Wille T, Koller M, Thiermann H (2016) Toxicology of organophosphorus compounds in view of an increasing terrorist threat. Arch Toxicol 90:2131–2145. https://doi.org/10.1007/s00204-016-1772-1
Yamada H, Urata C, Aoyama Y et al (2012) Preparation of colloidal mesoporous silica nanoparticles with different diameters and their unique degradation behavior in static aqueous systems. Chem Mater 24:1462–1471. https://doi.org/10.1021/cm3001688
Yanagisawa T, Shimizu T, Kuroda K, Kato C (1990) Trimethylsilyl derivatives of alkyltrimethylammonium-kanemite complexes and their conversion to microporous SiO2 materials. BCSJ 63:1535–1537. https://doi.org/10.1246/bcsj.63.1535
Yang J, Fan L, Wang F et al (2016) Rapid-releasing of HI-6 via brain-targeted mesoporous silica nanoparticles for nerve agent detoxification. Nanoscale 8:9537–9547. https://doi.org/10.1039/C5NR06658A
Yang S, Li X, Zeng G et al (2021) Materials Institute Lavoisier (MIL) based materials for photocatalytic applications. Coord Chem Rev 438:213874. https://doi.org/10.1016/j.ccr.2021.213874
Zdarova Karasova J, Kassa J, Hepnarova V et al (2022) Toxicity, pharmacokinetics, and effectiveness of the ortho-chlorinated bispyridinium oxime, K870. Food Chem Toxicol 167:113236. https://doi.org/10.1016/j.fct.2022.113236
Zhang Y, Wang J, Bai X et al (2012) Mesoporous silica nanoparticles for increasing the oral bioavailability and permeation of poorly water soluble drugs. Mol Pharm 9:505–513. https://doi.org/10.1021/mp200287c
Zhang RH, Li LQ, Wang C et al (2015) Pretreatment with huperzine A-loaded poly(lactide-co-glycolide) nanoparticles protects against lethal effects of soman-induced in mice. Key Eng Mater 645–646:1374–1382. https://doi.org/10.4028/www.scientific.net/KEM.645-646.1374
Zhang X, Xu X, Li S et al (2018) A systematic evaluation of the biocompatibility of cucurbit[7]uril in mice. Sci Rep 8:8819. https://doi.org/10.1038/s41598-018-27206-6
Zhang Y, He J, Shen L et al (2021) Brain-targeted delivery of obidoxime, using aptamer-modified liposomes, for detoxification of organophosphorus compounds. J Control Release 329:1117–1128. https://doi.org/10.1016/j.jconrel.2020.10.039
Zhao Y, Trewyn BG, Slowing II, Lin VS-Y (2009) Mesoporous silica nanoparticle-based double drug delivery system for glucose-responsive controlled release of insulin and cyclic AMP. J Am Chem Soc 131:8398–8400. https://doi.org/10.1021/ja901831u
Zhao D, Liu J, Zhang L et al (2022) Loading and sustained release of pralidoxime chloride from swellable MIL-88B(Fe) and its therapeutic performance on mice poisoned by neurotoxic agents. Inorg Chem 61:1512–1520. https://doi.org/10.1021/acs.inorgchem.1c03227
Zhao D, Liu J, Zhou Y et al (2023) Penetrating the blood–brain barrier for targeted treatment of neurotoxicant poisoning by nanosustained-released 2-PAM@VB1-MIL-101-NH2(Fe). ACS Appl Mater Interfaces. https://doi.org/10.1021/acsami.2c18929
Zheng M, Pan M, Zhang W et al (2021) Poly(α-l-lysine)-based nanomaterials for versatile biomedical applications: current advances and perspectives. Bioact Mater 6:1878–1909. https://doi.org/10.1016/j.bioactmat.2020.12.001
Zhi K, Raji B, Nookala AR et al (2021) PLGA nanoparticle-based formulations to cross the blood–brain barrier for drug delivery: from R&D to cGMP. Pharmaceutics 13:500. https://doi.org/10.3390/pharmaceutics13040500
Zhou “Joe” H-C, Kitagawa S (2014) Metal-organic frameworks (MOFs). Chem Soc Rev 43:5415–5418. https://doi.org/10.1039/C4CS90059F
Zhu H, Ka B, Murad F (2007) Nitric oxide accelerates the recovery from burn wounds. World J Surg 31:624–631. https://doi.org/10.1007/s00268-007-0727-3
Zhuang Q, Franjesevic AJ, Corrigan TS et al (2018) Demonstration of in vitro resurrection of aged acetylcholinesterase after exposure to organophosphorus chemical nerve agents. J Med Chem 61:7034–7042. https://doi.org/10.1021/acs.jmedchem.7b01620
Zorbaz T, Malinak D, Maraković N et al (2018) Pyridinium oximes with ortho-positioned chlorine moiety exhibit improved physicochemical properties and efficient reactivation of human acetylcholinesterase inhibited by several nerve agents. J Med Chem 61:10753–10766. https://doi.org/10.1021/acs.jmedchem.8b01398
Zorbaz T, Mišetić P, Probst N et al (2020) Pharmacokinetic evaluation of brain penetrating morpholine-3-hydroxy-2-pyridine oxime as an antidote for nerve agent poisoning. ACS Chem Neurosci 11:1072–1084. https://doi.org/10.1021/acschemneuro.0c00032
Zorbaz T, Malinak D, Hofmanova T et al (2022) Halogen substituents enhance oxime nucleophilicity for reactivation of cholinesterases inhibited by nerve agents. Eur J Med Chem 238:114377. https://doi.org/10.1016/j.ejmech.2022.114377
Acknowledgements
This study was supported by the Czech Science Foundation (Grant No. GA22-14568S) and Operational Programme “Development of the Internal Grant Agency of the University of Hradec Kralove” (Reg. No. CZ.02.2.69/0.0/0.0/19_073/0016949, project IGRA-TYM-2021001). Figures 9, 11, 14, 15, and TOC figure were created using BioRender.com.
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Prchalova, E., Kohoutova, Z., Knittelova, K. et al. Strategies for enhanced bioavailability of oxime reactivators in the central nervous system. Arch Toxicol 97, 2839–2860 (2023). https://doi.org/10.1007/s00204-023-03587-0
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DOI: https://doi.org/10.1007/s00204-023-03587-0