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Conjugation of haloperidol to PEG allows peripheral localisation of haloperidol and eliminates CNS extrapyramidal effects.
Journal of Controlled Release ( IF 10.8 ) Pub Date : 2020-02-26 , DOI: 10.1016/j.jconrel.2020.02.037
Az Alddien Natfji 1 , Dmitry O Nikitin 2 , Irina I Semina 2 , Rouslan I Moustafine 3 , Vitaliy V Khutoryanskiy 4 , Hong Lin 1 , Gary J Stephens 1 , Kimberly A Watson 5 , Helen M I Osborn 1 , Francesca Greco 1
Affiliation  

We have previously reported the synthesis of a poly(ethylene glycol)-haloperidol (PEG-haloperidol) conjugate that retained affinity for its target D2 receptor and was stable in simulated physiological conditions. We hypothesised that this polymer-drug conjugate would localise haloperidol's activity either centrally or peripherally, dependent on the location of administration, due to the polymer preventing penetration through the blood-brain barrier (BBB). Herein, we validate this hypothesis using in vitro and in vivo studies. We first demonstrate, via a [35S]GTPγS-binding assay, that drug activity is retained after conjugation to the polymer, supportive of retention of effective therapeutic ability. Specifically, the PEG-haloperidol conjugate (at 10 and 100 nM) was able to significantly inhibit dopamine-induced G-protein activation via D2 receptors, albeit with a loss of potency compared to the free haloperidol (~18-fold at 10 nM). This loss of potency was further probed and rationalised using molecular docking experiments, which indicated that conjugated haloperidol can still bind to the D2 receptors, albeit with a flipped orientation in the binding pocket within the receptor, which may explain the reduced activity. Finally, rat catalepsy studies confirmed the restricted permeation of the conjugate through the BBB in vivo. Rats treated intravenously with free haloperidol became cataleptic, whereas normal behaviour was observed in rats that received the PEG-haloperidol conjugate, suggesting that conjugation can effectively prevent unwanted central effects. Taken together these results demonstrate that conjugating small molecules to polymers is effective at prohibiting penetration of the drug through the BBB and is a valid targeting strategy for drugs to facilitate peripheral (or central) effects without inducing side effects in other compartments.

中文翻译:

氟哌啶醇与PEG的缀合允许氟哌啶醇的外周定位并消除了CNS锥体外系作用。

我们先前已经报道了聚(乙二醇)-氟哌啶醇(PEG-氟哌啶醇)缀合物的合成,该缀合物保留了对其靶D2受体的亲和力,并且在模拟的生理条件下稳定。我们假设该聚合物-药物偶联物将氟哌啶醇的活性定位在中心或外围,具体取决于给药位置,这是由于该聚合物可防止穿透血脑屏障(BBB)。本文中,我们使用体外和体内研究验证了这一假设。我们首先通过[35S]GTPγS结合试验证明,与聚合物结合后药物活性得以保留,从而支持有效治疗能力的保留。特别,PEG-氟哌啶醇偶联物(在10和100 nM时)能够通过D2受体显着抑制多巴胺诱导的G蛋白活化,尽管与游离氟哌啶醇相比(在10 nM时约18倍)丧失了效力。使用分子对接实验进一步探讨了这种效力丧失并进行了合理化,这表明缀合的氟哌啶醇仍可以与D2受体结合,尽管该受体内结合袋的方向发生了翻转,这可以解释其活性降低。最后,大鼠僵尸症研究证实了结合物在体内通过BBB的渗透受限。用游离氟哌啶醇静脉内治疗的大鼠具有镇静作用,而在接受PEG-氟哌啶醇缀合物的大鼠中观察到正常行为,这表明缀合物可以有效预防不良的中枢作用。
更新日期:2020-02-27
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