Smuggling Drugs into the Brain: An Overview of Ligands Targeting Transcytosis for Drug Delivery across the  Blood–Brain Barrier

Georgieva, Julia V.; Hoekstra, Dick; Zuhorn, Inge S.

doi:10.3390/pharmaceutics6040557

Cited by 162 publications

(131 citation statements)

References 132 publications

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“…Adsorptive-mediated endocytosis is instigated by the association of polycationic structures to negatively charged plasma membrane (45). Since glioma cells express GLUT1 and GLUT3 transporters, the obtained transport and uptake results would indicate that the uptake of the optimized glycosylated liposomes was mediated by both transcytosis and adsorptive endocytosis (46).…”

Section: C6 Glioma Cellular Uptakementioning

confidence: 95%

Glycosylated Sertraline-Loaded Liposomes for Brain Targeting: QbD Study of Formulation Variabilities and Brain Transport

et al. 2016

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Abstract. Effectiveness of CNS-acting drugs depends on the localization, targeting, and capacity to be transported through the blood-brain barrier (BBB) which can be achieved by designing brain-targeting delivery vectors. Hence, the objective of this study was to screen the formulation and process variables affecting the performance of sertraline (Ser-HCl)-loaded pegylated and glycosylated liposomes. The prepared vectors were characterized for Ser-HCl entrapment, size, surface charge, release behavior, and in vitro transport through the BBB. Furthermore, the compatibility among liposomal components was assessed using SEM, FTIR, and DSC analysis. Through a thorough screening study, enhancement of SerHCl entrapment, nanosized liposomes with low skewness, maximized stability, and controlled drug leakage were attained. The solid-state characterization revealed remarkable interaction between SerHCl and the charging agent to determine drug entrapment and leakage. Moreover, results of liposomal transport through mouse brain endothelialpolyoma cells demonstrated greater capacity of the proposed glycosylated liposomes to target the cerebellar due to its higher density of GLUT1 and higher glucose utilization. This transport capacity was confirmed by the inhibiting action of both cytochalasin B and phenobarbital. Using C6 glioma cells model, flow cytometry, time-lapse live cell imaging, and in vivo NIR fluorescence imaging demonstrated that optimized glycosylated liposomes can be transported through the BBB by classical endocytosis, as well as by specific transcytosis. In conclusion, the current study proposed a thorough screening of important formulation and process variabilities affecting brain-targeting liposomes for further scale-up processes.

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Section: C6 Glioma Cellular Uptakementioning

confidence: 95%

Glycosylated Sertraline-Loaded Liposomes for Brain Targeting: QbD Study of Formulation Variabilities and Brain Transport

et al. 2016

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“…Numerous analogues of the endogenous ligands, or of peptidomimetic antibodies (i.e. antibodies designed to mimic a peptide) that bind and activate the receptor-mediated transporters have been developed for drug delivery over three decades of research, [286] with numerous animal studies performed including in primates. (Such ligands are sometimes referred to as “molecular Trojan horses” because of their ability to ferry conjugated drugs across the BBB.)…”

Section: Breaching Biological Barriers Other Than Skinmentioning

confidence: 99%

Getting Drugs Across Biological Barriers

et al. 2017

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The delivery of drugs to a target site frequently involves crossing biological barriers. The degree and nature of the impediment to flux, as well as the potential approaches to overcoming it, depend on the tissue, the drug, and numerous other factors. Here we present an overview of approaches that have been taken to crossing biological barriers, with special attention to transdermal drug delivery. Technology and knowledge pertaining to addressing these issues in a variety of organs could have a significant clinical impact.

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“…This synergistic effect was also observed for the efflux of lapatinib [35] , imatinib [36] , vandetanib [37] , and regorafenib [38] . In addition to P-gp and BCRP, multidrug resistance protein 4/5 (MRP4/5), another major efflux transporter in the BBB endothelium, is drawing increasing attention in recent years [39][40][41] . Although administration of P-gp and BCRP inhibitors increased the K p,uu value of 3-OH-NBP to approximately 0.4, it was still <1.0.…”

Section: Discussionmentioning

confidence: 99%

Isomer-selective distribution of 3-n-butylphthalide (NBP) hydroxylated metabolites, 3-hydroxy-NBP and 10-hydroxy-NBP, across the rat blood-brain barrier

Diao

Zhong

et al. 2015

Acta Pharmacol Sin

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Aim: To investigate the mechanisms underlying the isomer-selective distribution of 3-n-butylphthalide (NBP) hydroxylated metabolites, 3-hydroxy-NBP (3-OH-NBP) and 10-hydroxy-NBP (10-OH-NBP), across the blood brain barrier (BBB). Methods: After oral administration of NBP (20 mg/kg) to rats, the pharmacokinetics of two major hydroxylated metabolites, 3-OH-NBP and 10-OH-NBP, in plasma and brains were investigated. Plasma and brain protein binding of 3-OH-NBP and 10-OH-NBP was also assessed. To evaluate the influences of major efflux transporters, rats were pretreated with the P-gp inhibitor tariquidar (10 mg/kg, iv) and BCRP inhibitor pantoprazole (40 mg/kg, iv), then received 3-OH-NBP (12 mg/kg, iv) or 10-OH-NBP (3 mg/kg, iv). The metabolic profile of NBP was investigated in rat brain homogenate. Results: After NBP administration, the plasma exposure of 3-OH-NBP was 4.64 times that of 10-OH-NBP, whereas the brain exposure of 3-OH-NBP was only 11.8% of 10-OH-NBP. In the rat plasma, 60%±5.2% of 10-OH-NBP was unbound to proteins versus only 22%±2.3% of 3-OH-NBP being unbound, whereas in the rat brain, free fractions of 3-OH-NBP and 10-OH-NBP were 100%±9.7% and 49.9%±14.1%, respectively. In the rats pretreated with tariquidar and pantoprazole, the unbound partition coefficient K p,uu of 3-OH-NBP was significantly increased, while that of 10-OH-NBP showed a slight but not statistically significant increase. Incubation of rat brain homogenate with NBP yielded 3-OH-NBP but not 10-OH-NBP. Conclusion: The isomer-selective distribution of 10-OH-NBP and 3-OH-NBP across the BBB of rats is mainly attributed to the differences in plasma and brain protein binding and the efflux transport of 3-OH-NBP. The abundant 10-OH-NBP is not generated in rat brains.

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Smuggling Drugs into the Brain: An Overview of Ligands Targeting Transcytosis for Drug Delivery across the Blood–Brain Barrier

Cited by 162 publications

References 132 publications

Glycosylated Sertraline-Loaded Liposomes for Brain Targeting: QbD Study of Formulation Variabilities and Brain Transport

Glycosylated Sertraline-Loaded Liposomes for Brain Targeting: QbD Study of Formulation Variabilities and Brain Transport

Getting Drugs Across Biological Barriers

Isomer-selective distribution of 3-n-butylphthalide (NBP) hydroxylated metabolites, 3-hydroxy-NBP and 10-hydroxy-NBP, across the rat blood-brain barrier

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