2-(2-Cholesteroxyethoxyl)ethyl-3′-S-glutathionylpropionate (COXP) for brain-targeting liposomes

The blood-brain barrier (BBB) poses a challenge for the treatment of cerebrovascular diseases including cerebral ischemia-reperfusion injury, Parkinson's syndrome, and cerebral tumors. Nanotechnology has developed as a promising strategy for drug delivery applications to the brain, especially liposomes (Lps) that have shown an intrinsic ability to cross the BBB. Angiopep-2 (ANG), a ligand for low-density lipoprotein receptor-related protein-1 (LRP1), is a good prospect for use as a targeting ligand for brain delivery using Lps. It was also reported that Polysorbate 80 (Tween 80, T80) plays a special role in brain targeting. Moreover, the nasal drug delivery method has attracted increased attention with its brain targeting capability in the clinical treatment of cerebrovascular diseases. The aim of this work was to evaluate the capability of Angiopep-conjugated Polysorbate 80-Coated Liposomes in the delivery of cyclovirobuxine D across the BBB in vitro and in vivo. For this purpose, we first synthesized DSPE-PEG2000-Angiopep-2 then cyclovirobuxine D was encapsulated in Angiopep-conjugated Polysorbate 80-Coated Liposomes (T80-An2-CVB-D-Lps) prepared by thin film evaporation and an ultrasonic technique. Formulations were characterized in terms of encapsulation efficiency, transmission electron microscope (TEM) morphology, size distribution, and zeta potential. Angiopep-conjugated Polysorbate 80-Coated Liposomes enhanced in vitro BBB transport of CVB-D compared to the nontargeted liposomes and the CVB-D solution in the BBB model consisting of brain microvascular endothelial (bEnd.3) cells. To evaluate the brain targeting of T80-An2-CVB-D-Lps in vivo, microdialysis samples were collected from the striatum and blood simultaneously. Rats were dosed with brain-targeting liposomes, CVB-D liposomes and CVB-D solution by intranasal administration and with brain-targeting liposomes by intravenous injection. The results showed that T80-An2-CVB-D-Lps were spherical, small (approximately 80 nm), homogeneously dispersed, negatively charged and possessed a high encapsulation efficiency. T80-An2-CVB-D-Lps crossed the BBB model better than the other treatments did. In addition, in a pharmacodynamic study, there was a higher AUC in the brain after T80-An2-CVB-D-Lps by intranasal administration. In conclusion, T80-An2-Lps can enhance the BBB permeability and improve the transport of CVB-D to the brain. This coadministration strategy can be utilized to enhance the brain accumulation in other cerebrovascular diseases.

Testing of a hypothesis for osmotic opening of the blood-brain barrier.

The brain targeting drug delivery system is the technique and process to deliver the drug into brain or central nerves system (CNS). The main problem arise during brain targeting in case of several brain related diseases and disorders such as CNS malignancy, brain abscess, multiple sclerosis, schizophrenia etc. selective and limiting permeation nature of barriers i.e. blood brain barrier (BBB) and blood cerebrospinal fluid barrier (BCSF), these two barriers only allow highly lipophilic molecule enters into brain and is one of the greatest clinical impediment of treatment of brain and CNS diseases and disorders. To treated this type of diseases and disorders drugs are targeted into brain and drug must be cross these two barriers they’re by different types of approaches are used to delivered drug molecules.Aim of research. The main aim of this review paper is to compile all the approaches, strategies and techniques used for brain targeted drug delivery in a single paper/ article.Material and method. To prepare this manuscript, various keywords were searched in different engines such as Google, Yahoo and Bing etc. The available information in public domain was collected and classified according to brain drug delivery system. This review deals with approaches and current strategies used to enhance the brain targeted drug delivery system. The approaches for brain targeting – invasive, non- invasive and miscellaneous techniques, by using these approaches enhance the drugs delivery and drugs are easily across BBB and BCSF.Result. The different type of approaches and strategies used to enhance the drug delivery into brain and CNS. All these techniques described in this paper are applied for overcoming the problems that arises during treatment of brain related diseases. This review paper has a list of different types of models (In-vitro and In-vivo) used in study of brain and CNS drug delivery.Conclusions. Drug delivery to brain for treating a various diseases and disorders are very difficult and challenging because the delivery of drug molecules must be pass through the BBB and BCSF. Overcome this difficulties and challenges certain approaches and technique such as invasive, non-invasive, intranasal delivery of drug, ocular delivery of drug and focused ultrasound technique are used to brain targeting. They are help to penetrate the drug molecule through BBB and CSF very easily and enhance the efficacy of treatment. This review article covered current approaches and strategies of brain targeting drug delivery in past five to ten years. These approaches and strategies are used to the brain delivery of drug, proteins, peptides, amino acids, etc.

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 Ser-HCl entrapment, nanosized liposomes with low skewness, maximized stability, and controlled drug leakage were attained. The solid-state characterization revealed remarkable interaction between Ser-HCl 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.

Blood–brain barrier (BBB) is a distinguishing checkpoint that segregates peripheral organs from neural compartment. It protects the central nervous system from harmful ambush of antigens and pathogens. Owing to such explicit selectivity, the BBB hinders passage of various neuroprotective drug molecules that escalates into poor attainability of neuroprotective agents towards the brain. However, few molecules can surpass the BBB and gain access in the brain parenchyma by exploiting surface transporters and receptors. For successful development of brain-targeted therapy, understanding of BBB transporters and receptors is crucial. This review focuses on the transporter and receptor–based mechanistic pathway that can be manoeuvred for better comprehension of reciprocity of receptors and nanotechnological vehicle delivery. Nanotechnology has emerged as one of the expedient noninvasive approaches for brain targeting via manipulating the hurdle of the BBB. Various nanovehicles are being reported for brain-targeted delivery such as nanoparticles, nanocrystals, nanoemulsion, nanolipid carriers, liposomes and other nanovesicles. Nanotechnology-aided brain targeting can be a strategic approach to circumvent the BBB without altering the inherent nature of the BBB.

The antiepileptic drug lamotrigine is a substrate of mouse and human breast cancer resistance protein (ABCG2)

Efficient neuronal targeting and transfection using RVG and transferrin-conjugated liposomes

The blood–brain barrier (BBB) is part of a neurovascular structure located in the brain’s micro vessels, that is essential to maintain brain homeostasis, but prevents the brain uptake of most drugs. Because of its importance in neuro-pharmacotherapy, the BBB has been the subject of extensive research since its discovery over 100 years ago. Major advances in understanding the structure and function of the barrier have been made. Drugs are re-designed to cross the BBB. However, despite these efforts, overcoming the BBB efficiently to treat brain diseases safely remains challenging. The majority of BBB research studies focus on the BBB as a homogenous structure throughout the different brain regions. However, this simplification may lead to an inadequate understanding of the BBB function with significant therapeutic consequences. From this perspective, we analyzed the gene and protein expression profiles of the BBB in the micro vessels from the brains of mice that were isolated from two different brain regions, namely the cortex and the hippocampus. The expression profile of the inter-endothelial junctional protein (claudin-5), three ABC transporters (P-glycoprotein, Bcrp and Mrp-1), and three BBB receptors (lrp-1, TRF and GLUT-1) were analyzed. Our gene and protein analysis showed that the brain endothelium in the hippocampus exhibits different expression profiles compared to the brain cortex. Specifically, brain endothelial cells (BECs) of the hippocampus express higher gene levels of abcb1, abcg2, lrp1, and slc2a1 compared to the BECs of the cortex regions with a trend of increase for claudin-5, while BECs of the cortex express higher gene levels of abcc1 and trf compared to the hippocampus. At the protein levels, the P-gp expression was found to be significantly higher in the hippocampus compared to the cortex, while TRF was found to be up-regulated in the cortex. These data suggest that the structure and function of the BBB are not homogeneous, and imply that drugs are not delivered similarly among the different brain regions. Appreciation of the BBB heterogeneity by future research programs is thus critical for efficient drug delivery and the treatment of brain diseases.

Inability to achieve therapeutic concentrations of a medication in the brain due to the blood brain barrier (BBB) is the major cause of treatment failure for most brain diseases. The BBB prevents almost 98% of small molecule drugs and almost all large molecule therapeutics from entering the brain. Modifying a drug delivery system with a brain targeting agent has been an effective approach in developing a brain targeting drug delivery system. Most of the brain targeting agents were developed based on a receptor- or carrier-mediated endocytosis process at the BBB. These endocytosis processes are transporting mechanisms for transporting endogenous molecules into the brain. They include those for transporting transferrin, LDL (low density lipoprotein), insulin, etc., with transferrin receptor-mediated endocytosis being the most investigated and successful one for developing a brain targeting agent. The Na+-dependent glutathione transporter is present on the luminal side of the capillary endothelial cells of the brain, kidneys, and small intestine while its presence on the luminal side of the capillary endothelial cells of other organs is very minimal. This organ distribution difference enables the brain, kidneys and small intestines to sequester GSH from the blood circulation to meet the need of these organs for GSH, and provide a solid foundation for developing organ selective agents for these organs in general. This review provides an overview of the GSH transporter and the status of GSH transporter-based brain targeting drug delivery systems with the intention of bringing the field to the attention of a medicinal chemist for his/her expertise in organic synthesis, ligand identification and optimization.

PurposeOrganophosphorus compounds (OPs) is a serious threat to human health and life safety, but because of the existence of blood-brain barrier, most of the therapeutic drugs cannot enter the center, reactivate centrally located toxic acetylcholinesterase (AChE), it is urgent to find an efficient treatment method. MethodsThe c(RGDyK) cyclic peptide modified HI-6-loaded brain targeting liposomes [c(RGDyK)-PEG2000HI-6-lipo] were prepared by ammonium sulfate gradient method. The in vitro blood-brain barrier (BBB) model was established, and the function of the liposomes was evaluated. The animal model of DDVP poisoning was established, and the central toxic enzyme reactivation ability of c(RGDyK)-PEG2000HI-6-lipo by both the intravenous and nasal administration route was verified. ResultsThe HI-6-loaded liposomes with brain targeting function were successfully synthesized and prepared with high encapsulation efficiency (70.23 ± 2.18%), drug loading (2.86 ± 0.07)%, average particle size 242.9 nm (polydispersion index 0.149), and ζ potential -16.2 mV. Combined with the in vitro and in vivo studies, the c(RGDyK)-PEG2000HI-6-lipo has better ability to cross the BBB. In addition, compared with intravenous injection, nasal administration was proved to be more effective against organophosphorus poisoning, and the reactivation rate of brain acetylcholinesterase reached (26.19 ± 7.70)%. ConclusionThe prepared c(RGDyK)-PEG2000HI-6-lipo has a better ability to cross BBB. Nasal administration, as a way to bypass the BBB and directly deliver drugs into the brain, effectively improves the bioavailability of HI-6 in the brain. This study holds promise by providing a non-invasive approach to deliver water-soluble oxime antidote into the brain and reactivate central acetylcholinesterase via the naso-brain route.

Crossing Barriers From blood-to-brain and academia-to-industry

Delivering Drugs Into the Brain: Barriers and Possibilities

The blood-brain barrier (BBB) exerts its central nervous system (CNS) protective function as it hinders the delivery of diagnostic and therapeutic agents to the brain. Gene therapy could be applied in conquering brain diseases such as neurodegenerative diseases and brain tumors by up- or down-regulating expression of diseased proteins. With the development of nanotechnology during the last thirty years, the nanocarriers for delivering drugs including gene medicines make it possible to transport drugs across the BBB. The nonviral nano-scaled gene delivery systems hold great promise for treating brain diseases due to their safety and convenience. Several brain targeting strategies, such as adsorptive- and receptor-mediated pathways have been developed to improve the brain targeting efficiency of non-viral gene delivery systems. In this review, the non-viral nanocarriers are focused for gene delivery and several possible strategies are discussed to achieve brain targeting effects. Finally, the applications of gene therapy in several brain diseases will be introduced. Keywords: Blood-brain barrier, brain-targeting, gene therapy, nanoparticles, non-viral gene delivery, receptor-mediated endocytosis, central nervous system, herpes virus, lentiviruses, adeno-associated, immuno-genicity, viral cationic liposome, polymer vectors, lipoplexes, polyplexes, adsorptive-mediated endocytosis, Parkinson's disease, Alzheimer's disease, brain tumors, monocytes, Cationic Lipids, attenuation, hippocampus, Polyethylenimine (PEI), Polyamidoamine (PAMAM), red blood cells (RBCs), Adsorptive Mediated Endocytosis, HIV-1 Trans-Activating Transcriptional Activator, Antennapedia Peptide, Low Molecular Weight Protamine (LMWP), Transferrin Receptors, Lactoferrin (Lf) Receptors, Insulin Receptors, Acetylcholine Receptor, Low Density Lipoprotein (LDL) Receptor Family, Leptin Receptors, Dopamine, Neurotrophic Factors

Cholesterol is essential for neuronal physiology, both during development and in the adult life: as a major component of cell membranes and precursor of steroid hormones, it contributes to the regulation of ion permeability, cell shape, cell-cell interaction, and transmembrane signaling. Consistently, hereditary diseases with mutations in cholesterol-related genes result in impaired brain function during early life. In addition, defects in brain cholesterol metabolism may contribute to neurological syndromes, such as Alzheimer's disease (AD), Huntington's disease (HD), and Parkinson's disease (PD), and even to the cognitive deficits typical of the old age. In these cases, brain cholesterol defects may be secondary to disease-causing elements and contribute to the functional deficits by altering synaptic functions. In the first part of this review, we will describe hereditary and non-hereditary causes of cholesterol dyshomeostasis and the relationship to brain diseases. In the second part, we will focus on the mechanisms by which perturbation of cholesterol metabolism can affect synaptic function.

2-(2-Cholesteroxyethoxyl)ethyl 3′-S-glutathionylpropionate and its self-assembled micelles for brain delivery: Design, synthesis and evaluation