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https://www.readbyqxmd.com/read/28101766/crossing-the-blood-brain-barrier-recent-advances-in-drug-delivery-to-the-brain
#1
Mayur M Patel, Bhoomika M Patel
CNS disorders are on the rise despite advancements in our understanding of their pathophysiological mechanisms. A major hurdle to the treatment of these disorders is the blood-brain barrier (BBB), which serves as an arduous janitor to protect the brain. Many drugs are being discovered for CNS disorders, which, however fail to enter the market because of their inability to cross the BBB. This is a pronounced challenge for the pharmaceutical fraternity. Hence, in addition to the discovery of novel entities and drug candidates, scientists are also developing new formulations of existing drugs for brain targeting...
January 18, 2017: CNS Drugs
https://www.readbyqxmd.com/read/28069747/a-targeted-rnai-screen-identifies-factors-affecting-diverse-stages-of-receptor-mediated-transcytosis
#2
Bradlee Nelms, Natasha Furtado Dalomba, Wayne Lencer
Endosome transport by transcytosis is the primary mechanism by which proteins and other large cargo traverse epithelial barriers in normal tissue. Transcytosis is also essential for establishing and maintaining membrane polarity in epithelia and other polarized cells. To identify novel components of this pathway, we conducted a high-throughput RNA interference screen for factors necessary for the bidirectional transcytosis of IgG by the Fcγ receptor FcRn. This screen identified 23 genes whose suppression resulted in a reproducible decrease in FcRn-mediated transcytosis...
January 9, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/28042336/bivalent-brain-shuttle-increases-antibody-uptake-by-monovalent-binding-to-the-transferrin-receptor
#3
Greta Hultqvist, Stina Syvänen, Xiaotian T Fang, Lars Lannfelt, Dag Sehlin
The blood-brain barrier (BBB) is an obstacle for antibody passage into the brain, impeding the development of immunotherapy and antibody-based diagnostics for brain disorders. In the present study, we have developed a brain shuttle for active transport of antibodies across the BBB by receptor-mediated transcytosis. We have thus recombinantly fused two single-chain variable fragments (scFv) of the transferrin receptor (TfR) antibody 8D3 to the light chains of mAb158, an antibody selectively binding to Aβ protofibrils, which are involved in the pathogenesis of Alzheimer's disease (AD)...
2017: Theranostics
https://www.readbyqxmd.com/read/28040636/protein-engineering-approaches-for-regulating-blood-brain-barrier-transcytosis
#4
REVIEW
Loukas I Goulatis, Eric V Shusta
The blood brain barrier (BBB) presents a challenge for the delivery of brain therapeutics. Trans-BBB delivery methods that use targeting vectors to coopt the vesicle trafficking machinery of BBB endothelial cells have been developed, but these are often hampered by limited flux through the BBB. A solution to this problem lies in the semi-rational engineering of BBB targeting vectors. Leveraging knowledge of intracellular trafficking, researchers have begun to tune selected binding properties of the vector-receptor interaction...
December 29, 2016: Current Opinion in Structural Biology
https://www.readbyqxmd.com/read/28017890/rigidity-of-polymer-micelles-affects-interactions-with-tumor-cells
#5
Tal Stern, Inon Kaner, Neta Laser Zer, Hila Shoval, Dvir Dror, Zakhariya Manevitch, Liraz Chai, Yifat Brill-Karniely, Ofra Benny
Controlling the interaction of drug delivery systems (DDS) with tissues is critical for the success of therapies. Specifically in cancer, due to the high density of the tumors, tissue penetration of DDS is critical and may be challenging. In previous work we have shown that Solidified Polymer Micelles (SPMs) rapidly internalize into cells and tissues. Using AFM analysis, in the present work we measured differences in rigidity of SPM compared with Wet Polymer Micelles (WPM). We further examined whether the semi-solid form of hydrated SPMs has an effect on the interaction with tumor cells both in mono-layer systems and in multi-layer clusters of cells as spheroids...
December 23, 2016: Journal of Controlled Release: Official Journal of the Controlled Release Society
https://www.readbyqxmd.com/read/27989702/development-of-novel-self-assembled-es-plga-hybrid-nanoparticles-for-improving-oral-absorption-of-doxorubicin-hydrochloride-by-p-gp-inhibition-in-vitro-and-in-vivo-evaluation
#6
Jia Wang, Lin Li, Lei Wu, Bingjun Sun, Yuqian Du, Jin Sun, Yongjun Wang, Qiang Fu, Peng Zhang, Zhonggui He
To increase the encapsulation efficiency and oral absorption of doxorubicin hydrochloride (DOX), a novel drug delivery system of enoxaparin sodium-PLGA hybrid nanoparticles (EPNs) was successfully designed. By introducing the negative polymer of enoxaparin sodium (ES) to form an electrostatic complex with the cationic drug, DOX, the encapsulation efficiency (93.78%) of DOX was significantly improved. The X-ray diffraction (XRD) results revealed that the DOX-ES complex was in an amorphous form. An in vitro release (pH6...
December 15, 2016: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/27976378/the-human-brain-endothelial-barrier-transcytosis-of-aav9-transduction-by-aav2-an-editorial-highlight-for-trafficking-of-adeno-associated-virus-vectors-across-a-model-of-the-blood-brain-barrier-a-comparative-study-of-transcytosis-and-transduction-using-primary
#7
EDITORIAL
Danielle Weber-Adrian, Stefan Heinen, Joseph Silburt, Zeinab Noroozian, Isabelle Aubert
Endothelial cells at the blood-brain barrier prevent the passage of adeno-associated virus 2 (AAV2) but not AAV9. This editorial highlights a study by Merkel et al. (2016) in which a barrier, composed of human brain microvascular endothelial cells in culture, was used to characterize the trafficking mechanisms leading primarily to transduction of endothelial cells for AAV2, and transcytosis for AAV9. Read the highlighted article 'Trafficking of adeno-associated virus vectors across a model of the blood-brain barrier; a comparative study of transcytosis and transduction using primary human brain endothelial cells' on doi: 10...
December 15, 2016: Journal of Neurochemistry
https://www.readbyqxmd.com/read/27966557/broadly-neutralizing-antibodies-suppress-post-transcytosis-hiv-1-infectivity
#8
V Lorin, M Malbec, C Eden, T Bruel, F Porrot, M S Seaman, O Schwartz, H Mouquet
Broadly neutralizing antibodies (bNAbs) offer promising opportunities for preventing HIV-1 infection in humans. Immunoprophylaxis with potent bNAbs efficiently protects non-human primates from mucosal transmission even after repeated challenges. However, the precise mechanisms of bNAb-mediated viral inhibition in mucosal tissues are currently unknown. Here, we show that immunoglobulin (Ig)G and IgA bNAbs do not interfere with the endocytic transport of HIV-1 across epithelial cells, a process referred to as transcytosis...
December 14, 2016: Mucosal Immunology
https://www.readbyqxmd.com/read/27935765/gb3-binding-lectins-as-potential-carriers-for-transcellular-drug-delivery
#9
Stefan K Müller, Isabel Wilhelm, Thomas Schubert, Katharina Zittlau, Anne Imberty, Josef Madl, Thorsten Eierhoff, Roland Thuenauer, Winfried Römer
OBJECTIVES: Epithelial cell layers as well as endothelia forming the blood-brain barrier can drastically reduce the efficiency of drug targeting. Our goal was to investigate lectins recognizing the glycosphingolipid globotriaosylceramide (Gb3) for their potential as carriers for transcytotic drug delivery. METHODS: We utilized an in vitro model based on Madin-Darby canine kidney cells transfected with Gb3 synthase to characterize transcytosis of the Gb3-binding lectins LecA from Pseudomonas aeruginosa and the B-subunit of Shiga toxin (StxB)...
December 16, 2016: Expert Opinion on Drug Delivery
https://www.readbyqxmd.com/read/27923925/biliary-secretion-of-quasi-enveloped-human-hepatitis-a-virus
#10
Asuka Hirai-Yuki, Lucinda Hensley, Jason K Whitmire, Stanley M Lemon
: Hepatitis A virus (HAV) is an unusual picornavirus that is released from cells cloaked in host-derived membranes. These quasi-enveloped virions (eHAV) are the only particle type circulating in blood during infection, whereas only nonenveloped virions are shed in feces. The reason for this is uncertain. Hepatocytes, the only cell type known to support HAV replication in vivo, are highly polarized epithelial cells with basolateral membranes facing onto hepatic (blood) sinusoids and apical membranes abutting biliary canaliculi from which bile is secreted to the gut...
December 6, 2016: MBio
https://www.readbyqxmd.com/read/27916828/enhancing-anticancer-effect-of-gefitinib-across-the-blood-brain-barrier-model-using-liposomes-modified-with-one-%C3%AE-helical-cell-penetrating-peptide-or-glutathione-and-tween-80
#11
Kuan-Hung Lin, Shu-Ting Hong, Hsiang-Tsui Wang, Yu-Li Lo, Anya Maan-Yuh Lin, James Chih-Hsin Yang
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI), such as gefitinib, have been demonstrated to effectively treat the patients of extracranial non-small cell lung cancer (NSCLC). However, these patients often develop brain metastasis (BM) during their disease course. The major obstacle to treat BM is the limited penetration of anticancer drugs across the blood-brain barrier (BBB). In the present study, we utilized gefitinib-loaded liposomes with different modifications to improve gefitinib delivery across the in vitro BBB model of bEnd...
November 29, 2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/27869117/genome-wide-rnai-screen-reveals-alk1-mediates-ldl-uptake-and-transcytosis-in-endothelial-cells
#12
Jan R Kraehling, John H Chidlow, Chitra Rajagopal, Michael G Sugiyama, Joseph W Fowler, Monica Y Lee, Xinbo Zhang, Cristina M Ramírez, Eon Joo Park, Bo Tao, Keyang Chen, Leena Kuruvilla, Bruno Larriveé, Ewa Folta-Stogniew, Roxana Ola, Noemi Rotllan, Wenping Zhou, Michael W Nagle, Joachim Herz, Kevin Jon Williams, Anne Eichmann, Warren L Lee, Carlos Fernández-Hernando, William C Sessa
In humans and animals lacking functional LDL receptor (LDLR), LDL from plasma still readily traverses the endothelium. To identify the pathways of LDL uptake, a genome-wide RNAi screen was performed in endothelial cells and cross-referenced with GWAS-data sets. Here we show that the activin-like kinase 1 (ALK1) mediates LDL uptake into endothelial cells. ALK1 binds LDL with lower affinity than LDLR and saturates only at hypercholesterolemic concentrations. ALK1 mediates uptake of LDL into endothelial cells via an unusual endocytic pathway that diverts the ligand from lysosomal degradation and promotes LDL transcytosis...
November 21, 2016: Nature Communications
https://www.readbyqxmd.com/read/27868280/chlamydial-infection-enhances-expression-of-the-polymeric-immunoglobulin-receptor-pigr-and-transcytosis-of-iga
#13
Charles W Armitage, Connor P O'Meara, Kenneth W Beagley
PROBLEM: The pIgR mediates transport of IgA into the lumen of mucosal tissues preventing pathogenic infection. Despite this, the expression of pIgR during chlamydial infections of the male and female reproductive tracts remains poorly understood. METHOD OF STUDY: The expression of pIgR in response to hormone cycling or over the course of chlamydial infection was determined in vitro and in vivo by Western blot or immunohistochemistry. RESULTS: PIgR was upregulated in response to Chlamydia spp...
January 2017: American Journal of Reproductive Immunology: AJRI
https://www.readbyqxmd.com/read/27836572/neonatal-fc-receptor-fcrn-is-involved-in-intracellular-transport-of-the-fc-fusion-protein-aflibercept-and-its-transition-through-retinal-endothelial-cells
#14
Heidrun L Deissler, Gerhard K Lang, Gabriele E Lang
Retinal endothelial cells (REC) likely contribute to the clearance of intravitreally injected IgG. Because this is of high relevance to the pharmacokinetic assessment of the widely used therapeutic Fc fusion protein aflibercept, we studied its transport through immortalized bovine REC (iBREC) in detail. For shuttling of IgG or Fc fusion proteins like aflibercept, endothelial cells use the highly conserved neonatal Fc receptor (FcRn) also expressed in iBREC where it is down regulated by serum depletion. Therefore, we focused on studying intracellular localization and transport of aflibercept under conditions affecting its interaction with the FcRn...
November 9, 2016: Experimental Eye Research
https://www.readbyqxmd.com/read/27765902/delivery-of-a-peptide-drug-conjugate-targeting-the-blood-brain-barrier-improved-the-efficacy-of-paclitaxel-against-glioma
#15
Ying Li, Xuemin Zheng, Min Gong, Jianning Zhang
The challenge of effectively delivering therapeutic agents to the brain has created an entire field of active research devoted to overcoming the blood brain barrier (BBB) and efficiently delivering drugs to the brain. Angiopep-2 can trigger transcytosis and traverse the BBB by recognizing low-density lipoprotein related protein-1 (LRP-1) expressed on the brain capillary endothelial cells. Here, we designed a novel strategy for the delivery of drugs to the brain. The novel drug delivery system was a combination of a receptor-targeting ligand, such as low-density lipoprotein related protein 1, and a cell-penetrating peptide (CPP)...
October 17, 2016: Oncotarget
https://www.readbyqxmd.com/read/27750011/endogenous-polysialic-acid-based-micelles-for-calmodulin-antagonist-delivery-against-vascular-dementia
#16
Xiao-Juan Wang, Yin-Ping Gao, Nan-Nan Lu, Wei-Shuo Li, Ji-Fang Xu, Xiao-Ying Ying, Gang Wu, Mei-Hua Liao, Chao Tan, Ling-Xiao Shao, Ying-Mei Lu, Chen Zhang, Kohji Fukunaga, Feng Han, Yong-Zhong Du
Clinical treatment for vascular dementia still remains a challenge mainly due to the blood-brain barrier (BBB). Here, a micelle based on polysialic acid (PSA), which is a hydrophilic and endogenous carbohydrate polymer, was designed to deliver calmodulin antagonist for therapy of vascular dementia. PSA was first chemically conjugated with octadecylamine (ODA), and the obtained PSA-ODA copolymer could self-assemble into micelle in aqueous solution with a 120.0 μg/mL critical micelle concentration. The calmodulin antagonist loaded PSA-ODA micelle, featuring sustained drug release behavior over a period of 72 h with a 3...
December 28, 2016: ACS Applied Materials & Interfaces
https://www.readbyqxmd.com/read/27734392/analysis-of-transcytosis-of-ccn2-by-chondrocytes
#17
Kazumi Kawata, Satoshi Kubota, Masaharu Takigawa
Transcytosis is a mechanism for the transcellular transport of biomolecules. Analysis of transcytosis is frequently performed in cells with distinct polarity, such as brain endothelial cells. However, in cells without evident polarity, analysis of transcytosis has not been performed. Here, we describe a method for analyzing transcytosis of a CCN family protein through chondrocytic cells having no apparent polarity.
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/27732852/defective-transcytosis-of-app-and-lipoproteins-in-human-ipsc-derived-neurons-with-familial-alzheimer-s-disease-mutations
#18
Grace Woodruff, Sol M Reyna, Mariah Dunlap, Rik Van Der Kant, Julia A Callender, Jessica E Young, Elizabeth A Roberts, Lawrence S B Goldstein
We investigated early phenotypes caused by familial Alzheimer's disease (fAD) mutations in isogenic human iPSC-derived neurons. Analysis of neurons carrying fAD PS1 or APP mutations introduced using genome editing technology at the endogenous loci revealed that fAD mutant neurons had previously unreported defects in the recycling state of endocytosis and soma-to-axon transcytosis of APP and lipoproteins. The endocytosis reduction could be rescued through treatment with a β-secretase inhibitor. Our data suggest that accumulation of β-CTFs of APP, but not Aβ, slow vesicle formation from an endocytic recycling compartment marked by the transcytotic GTPase Rab11...
October 11, 2016: Cell Reports
https://www.readbyqxmd.com/read/27726119/passage-of-magnetic-tat-conjugated-fe3o4-sio2-nanoparticles-across-in-vitro-blood-brain-barrier
#19
Xueqin Zhao, Ting Shang, Xiaodan Zhang, Ting Ye, Dajin Wang, Lei Rei
Delivery of diagnostic or therapeutic agents across the blood-brain barrier (BBB) remains a major challenge of brain disease treatment. Magnetic nanoparticles are actively being developed as drug carriers due to magnetic targeting and subsequently reduced off-target effects. In this paper, we developed a magnetic SiO2@Fe3O4 nanoparticle-based carrier bound to cell-penetrating peptide Tat (SiO2@Fe3O4(-Tat)) and studied its fates in accessing BBB. SiO2@Fe3O4-Tat nanoparticles (NPs) exhibited suitable magnetism and good biocompatibility...
December 2016: Nanoscale Research Letters
https://www.readbyqxmd.com/read/27718541/trafficking-of-adeno-associated-virus-vectors-across-a-model-of-the-blood-brain-barrier-a-comparative-study-of-transcytosis-and-transduction-using-primary-human-brain-endothelial-cells
#20
Steven F Merkel, Allison M Andrews, Evan M Lutton, Dakai Mu, Eloise Hudry, Bradley T Hyman, Casey A Maguire, Servio H Ramirez
Developing therapies for central nervous system (CNS) diseases is exceedingly difficult because of the blood-brain barrier (BBB). Notably, emerging technologies may provide promising new options for the treatment of CNS disorders. Adeno-associated virus serotype 9 (AAV9) has been shown to transduce cells in the CNS following intravascular administration in rodents, cats, pigs, and non-human primates. These results suggest that AAV9 is capable of crossing the BBB. However, mechanisms that govern AAV9 transendothelial trafficking at the BBB remain unknown...
January 2017: Journal of Neurochemistry
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