Combination delivery of two oxime-loaded lipid nanoparticles: Time-dependent additive action for prolonged rat brain protection

• Published in: Journal of controlled release 2018-11, Vol.290, p.102-111
• Main Authors: Pashirova, Tatiana N., Braïki, Anissa, Zueva, Irina V., Petrov, Konstantin A., Babaev, Vasily M., Burilova, Evgenia A., Samarkina, Darya A., Rizvanov, Ildar Kh, Souto, Eliana B., Jean, Ludovic, Renard, Pierre-Yves, Masson, Patrick, Zakharova, Lucia Ya, Sinyashin, Oleg G.
• Format: Article
• Language: English
• Subjects: Acetylcholinesterase; Blood-brain barrier; Chemical Sciences; Organophosphorus agent; Oxime; Paraoxon; Solid-Lipid Nanoparticles
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2018.10.010

A novel approach for brain protection against poisoning by organophosphorus agents is developed based on the combination treatment of dual delivery of two oximes. Pralidoxime chloride (2-PAM) and a novel reactivator, 6-(5-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)pentyl)-3-hydroxy picolinaldehyde oxime (3-HPA), have been loaded in solid-lipid nanoparticles (SLNs) to offer distinct release profile and systemic half-life for both oximes. To increase the therapeutic time window of both oximes, SLNs with two different compartments were designed to load each respective drug. Oxime-loaded SLNs of hydrodynamic diameter between 100 and 160 nm and negative zeta potential (−30 to −25 mV) were stable for a period of 10 months at 4 °C. SLNs displayed longer circulation time in the bloodstream compared to free 3-HPA and free 2-PAM. Oxime-loaded SLNs were suitable for intravenous (iv) administration. Paraoxon-poisoned rats (0.8 × LD50) were treated with 3-HPA-loaded SLNs and 2-PAM+3-HPA-loaded SLNs at the dose of 3-HPA and 2-PAM of 5 mg/kg. Brain AChE reactivation up to 30% was slowly achieved in 5 h after administration of 3-HPA-SLNs. For combination therapy with two oximes, a time-dependent additivity and increased reactivation up to 35% were observed. [Display omitted]