Covalent Linkage of Apolipoprotein E to Albumin Nanoparticles Strongly Enhances Drug Transport into the Brain

Michaelis, Kerstin; Hoffmann, Michael M.; Dreis, Sebastian; Herbert, Elisabeth; Alyautdin, R. N.; Michaelis, Martin; Kreuter, J.; Langer, Klaus

doi:10.1124/jpet.105.097139

Cited by 326 publications

(191 citation statements)

References 39 publications

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“…The values of regional blood volumes used to correct brain radio activities were in accordance with those published previously [16,17]. Mice brains were divided into three regions, the two hemispheres and the cerebellum.…”

Section: Brain Distribution Studiesmentioning

confidence: 82%

Brain Targeting Potential of Intravenous Carbamazepine SNEDDS

Kumar¹,

Rambhau²

2017

J Mol Pharm Org Process Res

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Purpose: The objective of this study was to evaluate the ability of nano-droplets of Self Nano Emulsifying Drug Delivery System to diffuse into the brain tissue. Methods:The preconcentrate was prepared by dissolving oils, surfactants and cosolvents in 1:1 mixture of methanol and chloroform and flash evaporated at 50°C and was stored at room temperature until their use in subsequent studies. CSEDD with surfactant polysorbate-80 were radiolabelled with radioactive C18 triglyceride. The nanodroplets formed by CSEDD in 5% dextrose were subjected to evaluation in blood and brain. Results:The intravenous pharmacokinetics of carbamazepine in rats of CSEDD formulation generated high initial serum levels (5.25 mcg/ml) at 0.25 h when compared to C-Sol (3.91 mcg/ml) at 0.5 h. It was found that oil to surfactant ratio had an impact on the physical characteristics of the nano-emulsion formed. The brain levels of CBZ from optimized CSEDD were significantly high at all-time points when compared to plain solution. The initial levels of CBZ from CSEDD was 8.023 mcg/ml thereafter the levels were consistently high till 8 h and the initial levels of CBZ from plain solution was 3.62 mcg/ml followed by a gradual decline till 4 h evidently showing that the clearance of CBZ from CSEDD was reduced. The brain targeting index of CSEDD and solution were 3 and 2 respectively. The brain enhancement factor value was found to be 22.29 at 15 min revealing a very rapid penetration of CBZ into brain. Conclusions:This study proposes intravenous CSEDD as a new brain delivery system and highlights two requirements to design adequate delivery systems for long circulating properties of the carrier and appropriate surface characteristics to allow interactions with BBB endothelial cells.

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Section: Brain Distribution Studiesmentioning

confidence: 82%

Brain Targeting Potential of Intravenous Carbamazepine SNEDDS

Kumar¹,

Rambhau²

2017

J Mol Pharm Org Process Res

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“…140 The reason for such interaction is concluded to be due to the absorption of endogenic LDL from the plasma by polysorbate 80 and in the interaction with the brain endotheliocytes in accordance with the Trojan horse principle. The role of apoE has been demonstrated in work by Michaelis et al in 2006. 141 Two types of albumin nanoparticles coated with polysorbate 80 and particles with covalently bound apoE on their surface exhibited approximately equal ability to transport MD through the BBB.…”

Section: Polymeric Nanoparticlesmentioning

confidence: 99%

Nanoscale drug delivery systems and the blood–brain barrier

Alyautdin¹,

Khalin²,

Nafeeza³

et al. 2014

IJN

121

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The protective properties of the blood–brain barrier (BBB) are conferred by the intricate architecture of its endothelium coupled with multiple specific transport systems expressed on the surface of endothelial cells (ECs) in the brain’s vasculature. When the stringent control of the BBB is disrupted, such as following EC damage, substances that are safe for peripheral tissues but toxic to neurons have easier access to the central nervous system (CNS). As a consequence, CNS disorders, including degenerative diseases, can occur independently of an individual’s age. Although the BBB is crucial in regulating the biochemical environment that is essential for maintaining neuronal integrity, it limits drug delivery to the CNS. This makes it difficult to deliver beneficial drugs across the BBB while preventing the passage of potential neurotoxins. Available options include transport of drugs across the ECs through traversing occludins and claudins in the tight junctions or by attaching drugs to one of the existing transport systems. Either way, access must specifically allow only the passage of a particular drug. In general, the BBB allows small molecules to enter the CNS; however, most drugs with the potential to treat neurological disorders other than infections have large structures. Several mechanisms, such as modifications of the built-in pumping-out system of drugs and utilization of nanocarriers and liposomes, are among the drug-delivery systems that have been tested; however, each has its limitations and constraints. This review comprehensively discusses the functional morphology of the BBB and the challenges that must be overcome by drug-delivery systems and elaborates on the potential targets, mechanisms, and formulations to improve drug delivery to the CNS.

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“…The duration of drug action attained with the bifunctional PLGA nanoparticles was longer than that attained using other nanoparticulate systems. 107,108 Biodistribution studies of the bifunctional PLGA nanoparticles revealed that 6% of the total injected dose of loperamide was localized inside the brain parenchyma of rats. This phenomenon could be attributed to interactions between the bifunctional PLGA nanoparticles and sialic acid receptors in the brain.…”

Section: Sialic Acid-functional Plga Nanoparticlesmentioning

confidence: 99%

Concepts and practices used to develop functional PLGA-based nanoparticulate systems

Sah¹,

Thoma²,

Desu³

et al. 2013

IJN

194

127

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Abstract:The functionality of bare polylactide-co-glycolide (PLGA) nanoparticles is limited to drug depot or drug solubilization in their hard cores. They have inherent weaknesses as a drug-delivery system. For instance, when administered intravenously, the nanoparticles undergo rapid clearance from systemic circulation before reaching the site of action. Furthermore, plain PLGA nanoparticles cannot distinguish between different cell types. Recent research shows that surface functionalization of nanoparticles and development of new nanoparticulate dosage forms help overcome these delivery challenges and improve in vivo performance. Immense research efforts have propelled the development of diverse functional PLGA-based nanoparticulate delivery systems. Representative examples include PEGylated micelles/nanoparticles (PEG, polyethylene glycol), polyplexes, polymersomes, core-shelltype lipid-PLGA hybrids, cell-PLGA hybrids, receptor-specific ligand-PLGA conjugates, and theranostics. Each PLGA-based nanoparticulate dosage form has specific features that distinguish it from other nanoparticulate systems. This review focuses on fundamental concepts and practices that are used in the development of various functional nanoparticulate dosage forms. We describe how the attributes of these functional nanoparticulate forms might contribute to achievement of desired therapeutic effects that are not attainable using conventional therapies. Functional PLGA-based nanoparticulate systems are expected to deliver chemotherapeutic, diagnostic, and imaging agents in a highly selective and effective manner.

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Covalent Linkage of Apolipoprotein E to Albumin Nanoparticles Strongly Enhances Drug Transport into the Brain

Cited by 326 publications

References 39 publications

Brain Targeting Potential of Intravenous Carbamazepine SNEDDS

Brain Targeting Potential of Intravenous Carbamazepine SNEDDS

Nanoscale drug delivery systems and the blood–brain barrier

Concepts and practices used to develop functional PLGA-based nanoparticulate systems

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Covalent Linkage of Apolipoprotein E to Albumin Nanoparticles Strongly Enhances Drug Transport into the Brain

Cited by 326 publications

References 39 publications

Brain Targeting Potential of Intravenous Carbamazepine SNEDDS

Brain Targeting Potential of Intravenous Carbamazepine SNEDDS

Nanoscale drug delivery systems and the blood&ndash;brain barrier

Concepts and practices used to develop functional PLGA-based nanoparticulate systems

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Product

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Nanoscale drug delivery systems and the blood–brain barrier