Scopine as a Novel Brain-Targeting Moiety Enhances the Brain Uptake of Chlorambucil

Wang, Xinyi; Li, Jianbo; Xu, Chunping; Li, Yanping; Gong, Tao; Sun, Xun; Fu, Yao; He, Qin; Zhang, Zhirong

doi:10.1021/bc5004108

Cited by 14 publications

(11 citation statements)

References 41 publications

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“…Recently, many targeting moieties are being used to deliver drug into the brain efficiently. This was recognized with scopine, 14 monoclonal antibody 2C5, 15 the OX26 16 or R17217 antibodies, 16 glutathione, 17 and anti-transferrin. 16 , 18 These moieties were found to enhance the uptake of the pharmaceutical moieties up to 14.25-fold.…”

Section: Introductionmentioning

confidence: 99%

Targeting brain cells with glutathione-modulated nanoliposomes: in vitro and in vivo study

Salem¹,

Ahmed²,

Hassaballah³

et al. 2015

DDDT

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BackgroundThe blood–brain barrier prevents many drug moieties from reaching the central nervous system. Therefore, glutathione-modulated nanoliposomes have been engineered to enhance the targeting of flucytosine to the brain.MethodsGlutathione-modulated nanoliposomes were prepared by thin-film hydration technique and evaluated in the primary brain cells of rats. Lecithin, cholesterol, and span 65 were mixed at 1:1:1 molar ratio. The molar percentage of PEGylated glutathione varied from 0 mol% to 0.75 mol%. The cellular binding and the uptake of the targeted liposomes were both monitored by epifluorescent microscope and flow cytometry techniques. A biodistribution and a pharmacokinetic study of flucytosine and flucytosine-loaded glutathione–modulated liposomes was carried out to evaluate the in vivo brain-targeting efficiency.ResultsThe size of glutathione-modulated nanoliposomes was <100 nm and the zeta potential was more than −65 mV. The cumulative release reached 70% for certain formulations. The cellular uptake increased as molar percent of glutathione increased to reach the maximum at 0.75 mol%. The uptake of the targeted liposomes by brain cells of the rats was three times greater than that of the nontargeted liposomes. An in vivo study showed that the relative efficiency was 2.632±0.089 and the concentration efficiency was 1.590±0.049, and also, the drug-targeting index was 3.670±0.824.ConclusionOverall, these results revealed that glutathione-PEGylated nanoliposomes enhance the effective delivery of flucytosine to brain and could become a promising new therapeutic option for the treatment of the brain infections.

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Section: Introductionmentioning

confidence: 99%

Targeting brain cells with glutathione-modulated nanoliposomes: in vitro and in vivo study

Salem¹,

Ahmed²,

Hassaballah³

et al. 2015

DDDT

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“…CHLS may be transported by the unidentified H + /OC antiporter [70,71]. Although CHLS was hydrolyzed to CHL in brain to elicit the activity, unhydrolyzed CHLS retained the activity against glioma [74]. This means that the transporter recognition unit, scopine in this case, is located separately from the pharmacophore in the molecule.…”

Section: Delivery Of Prodrugs Into Brain Across the Bbb Using The Tramentioning

confidence: 94%

Intriguing possibilities and beneficial aspects of transporter-conscious drug design

Tashima¹

2015

Bioorganic & Medicinal Chemistry

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“…The brain perfusion method was according to our previous study [21]. Briefly, rats (250 ± 20 g) were anesthetized with chloral hydrate (350 mg/kg, i.p.…”

Section: In Situ Rat Brain Perfusion and Mechanism Studymentioning

confidence: 99%

“…The structural relationship among the four cyclic tertiary amines is that they all contain tertiary amines but have different chemical environment of nitrogen atom, especially, scopine has an extra oxygen ring compared with tropine. Moreover, scopine, has been proven to successfully increase the concentration of chlorambucil in the brain with superior anti-glioma activity and reduced systemic toxicity [21]. Thus, we used the four cyclic tertiary amines (scopine, tropine, quinuclidinol and piperidinol) to synthesize a series of cyclic tertiary amine conjugates and to elucidate their structure-function relationship in targeting the pyrilamine-sensitive H + /OC antiporter.…”

Section: Introductionmentioning

confidence: 99%

Pyrilamine-sensitive proton-coupled organic cation (H+/OC) antiporter for brain-specific drug delivery

Wang

et al. 2017

Journal of Controlled Release

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Blood-brain barrier (BBB) represents the greatest challenge that hampers therapeutic molecules entering the brain. Here, we described a novel brain-specific delivery strategy targeting to pyrilamine-sensitive H/OC antiporter to facilitate therapeutic molecules cross the BBB and penetrate into the brain. In this study, four cyclic tertiary amines were selected as the brain-targeting moieties to modify naproxen (NP), a non-steroidal anti-inflammatory drug. The obtained NP conjugates displayed cell uptake efficiencies over 144-fold higher than that of unmodified NP in endothelial cells. The cell uptake process of the conjugates was primarily driven by pyrilamine-sensitive H/OC antiporter in a pH-dependent, Na-independent, and membrane potential-independent pathway, which could be further inhibited by pyrilamine, propranolol, and imipramine. Moreover, the NP conjugates showed significantly higher AUC and C in the brain compared with unmodified NP, and significantly higher accumulation than NP in the in situ brain perfusion study. Also, the conjugates showed superior neuroprotective effect in vitro and in vivo. Thus, the chemical modification of therapeutics with a cyclic tertiary amine moiety represents a promising and efficient strategy for brain-specific drug delivery via pyrilamine-sensitive H/OC antiporter.

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Scopine as a Novel Brain-Targeting Moiety Enhances the Brain Uptake of Chlorambucil

Cited by 14 publications

References 41 publications

Targeting brain cells with glutathione-modulated nanoliposomes: in vitro and in vivo study

Targeting brain cells with glutathione-modulated nanoliposomes: in vitro and in vivo study

Intriguing possibilities and beneficial aspects of transporter-conscious drug design

Pyrilamine-sensitive proton-coupled organic cation (H+/OC) antiporter for brain-specific drug delivery

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