CNS Delivery Via Adsorptive Transcytosis

Hervé, Françoise; Ghinea, Nicolae; Scherrmann, Jean‐Michel

doi:10.1208/s12248-008-9055-2

Cited by 495 publications

(390 citation statements)

References 123 publications

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“…In polarized PBCECs, the basolateral transfer of rhASA is reduced by Man-6-P, indicating that a fraction of endosomal rhASA is transported to the basolateral membrane and exocytosed. As suggested for other polypeptides, the adsorptive-mediated pathway of rhASA might involve clathrin-dependent transport across the endosomal compartment and/or direct transport of transcytotic vesicles budding from caveolae (20).…”

Section: Discussionmentioning

confidence: 87%

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Transport of Arylsulfatase A across the Blood-Brain Barrier in Vitro

Matthes

Wölte

Böckenhoff

et al. 2011

Journal of Biological Chemistry

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Enzyme replacement therapy is an option to treat lysosomal storage diseases caused by functional deficiencies of lysosomal hydrolases as intravenous injection of therapeutic enzymes can correct the catabolic defect within many organ systems. However, beneficial effects on central nervous system manifestations are very limited because the blood-brain barrier (BBB) prevents the transfer of enzyme from the circulation to the brain parenchyma. Preclinical studies in mouse models of metachromatic leukodystrophy, however, showed that arylsulfatase A (ASA) is able to cross the BBB to some extent, thus reducing lysosomal storage in brain microglial cells. The present study aims to investigate the routing of ASA across the BBB and to improve the transfer in vitro using a well established cell culture model consisting of primary porcine brain capillary endothelial cells cultured on Transwell filter inserts. Passive apical-to-basolateral ASA transfer was observed, which was not saturable up to high ASA concentrations. No active transport could be determined. The passive transendothelial transfer was, however, charge-dependent as reduced concentrations of negatively charged monosaccharides in the N-glycans of ASA or the addition of polycations increased basolateral ASA levels. Adsorptive transcytosis is therefore considered to be the major transport pathway. Partial inhibition of the transcellular ASA transfer by mannose 6-phosphate indicated a second route depending on the insulin-like growth factor II/mannose 6-phosphate receptor, MPR300. We conclude that cationization of ASA and an increase of the mannose 6-phosphate content of the enzyme may promote blood-to-brain transfer of ASA, thus leading to an improved therapeutic efficacy of enzyme replacement therapy behind the BBB.

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Section: Discussionmentioning

confidence: 87%

“…The impact of charge on the transendothelial transfer rate is a hallmark of adsorptive transcytosis (20). This pathway involves adsorption of a compound to the endothelial surface, a process which is disfavored by the repulsive forces between the negatively charged membrane and negative surface charges of the compound.…”

Section: Discussionmentioning

confidence: 99%

Transport of Arylsulfatase A across the Blood-Brain Barrier in Vitro

Matthes

Wölte

Böckenhoff

et al. 2011

Journal of Biological Chemistry

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“…Thus, the small size and highly lipophilic surface of T-NPs helped their distribution in the brain. Furthermore, high mitochondrial density in cerebral endothelial cells than in peripheral endothelia further assisted these T-NPs to accumulate in the brain efficiently (14,15). The distinctive properties of brain endothelium, high lipophilicity, and mitochondria-targeting properties of T-NPs provided selective targeting of these NPs to the brain.…”

Section: Significancementioning

confidence: 99%

Detouring of cisplatin to access mitochondrial genome for overcoming resistance

Marrache

Pathak

Dhar

2014

Proc. Natl. Acad. Sci. U.S.A.

214

209

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Chemoresistance of cisplatin therapy is related to extensive repair of cisplatin-modified DNA in the nucleus by the nucleotide excision repair (NER). Delivering cisplatin to the mitochondria to attack mitochondrial genome lacking NER machinery can lead to a rationally designed therapy for metastatic, chemoresistant cancers and might overcome the problems associated with conventional cisplatin treatment. An engineered hydrophobic mitochondria-targeted cisplatin prodrug, Platin-M, was constructed using a strainpromoted alkyne-azide cycloaddition chemistry. Efficient delivery of Platin-M using a biocompatible polymeric nanoparticle (NP) based on biodegradable poly(lactic-co-glycolic acid)-block-polyethyleneglycol functionalized with a terminal triphenylphosphonium cation, which has remarkable activity to target mitochondria of cells, resulted in controlled release of cisplatin from Platin-M locally inside the mitochondrial matrix to attack mtDNA and exhibited otherwise-resistant advanced cancer sensitive to cisplatin-based chemotherapy. Identification of an optimized targeted-NP formulation with brain-penetrating properties allowed for delivery of Platin-M inside the mitochondria of neuroblastoma cells resulting in ∼17 times more activity than cisplatin. The remarkable activity of Platin-M and its targeted-NP in cisplatin-resistant cells was correlated with the hyperpolarization of mitochondria in these cells and mitochondrial bioenergetics studies in the resistance cells further supported this hypothesis. This unique dual-targeting approach to controlled mitochondrial delivery of cisplatin in the form of a prodrug to attack the mitochondrial genome lacking NER machinery and in vivo distribution of the delivery vehicle in the brain suggested previously undescribed routes for cisplatinbased therapy.click chemistry | brain cancer | OXPHOS | pharmacokinetics T he cellular powerhouse, mitochondria, are implicated in the process of carcinogenesis because of their vital roles in energy production and apoptosis. Mitochondria are the key players in generating the cellular energy through oxidative phosphorylation (OXPHOS) that produces reactive oxygen species (ROS) as by-products. Mitochondrial DNA (mtDNA) plays significant roles in cell death and metastatic competence. The close proximity of mtDNA to the ROS production site makes this genome vulnerable to oxidative damage. Mitochondrial dysfunction and associated mtDNA depletion possibly reversibly control epigenetic changes in the nucleus that contributes to cancer development (1). Thus, targeting mtDNA could lead to novel and effective therapies for aggressive cancers. Cisplatin, a Food and Drug Administration-approved chemotherapeutic agent, is most extensively characterized as a DNA-damaging agent and the cytotoxicity of cisplatin is attributed to the ability to form interstrand and intrastrand nuclear DNA (nDNA) cross-links (2). The nucleotide excision repair (NER) pathway plays major roles in repairing cisplatin-nDNA adducts (3). Resistance to cisplatin can result fr...

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“…To enter the brain, nutrients and signaling molecules must engage specific transport systems on BBB cells (Broadwell, 1989;Hervé et al, 2008). Lipoproteins mediate interorgan transport of nutritional and signaling lipids, and also bear a variety of lipid-linked signaling molecules (Panáková et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Lipoprotein Particles Cross the Blood–Brain Barrier inDrosophila

Brankatschk

Eaton

2010

J. Neurosci.

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The blood-brain barrier (BBB) regulates passage of nutrients and signaling molecules from the circulation into the brain. Whether lipoproteins cross the BBB in vivo has been controversial, and no clear requirement for circulating lipoproteins in brain development has been shown. We address these issues in Drosophila, which has an functionally conserved BBB, and lipoproteins that resemble those of vertebrates. We show that the Drosophila lipoprotein lipophorin exists in two isoforms. Both isoforms cross the BBB, but accumulate on distinct subsets of cells within the brain. In addition to acting as a lipid carrier, lipophorin carries both sterol-linked and GPI-linked proteins into the circulation and transports them across the BBB. Finally, lipophorin promotes neuroblast proliferation by a mechanism that does not depend on delivery of dietary lipids. Transport of lipophorin and its cargo across the BBB represents a novel mechanism by which peripherally synthesized proteins might enter the brain and influence its development. Furthermore, lipid-linkage may be an efficient method to transport therapeutic molecules across the BBB.

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CNS Delivery Via Adsorptive Transcytosis

Cited by 495 publications

References 123 publications

Transport of Arylsulfatase A across the Blood-Brain Barrier in Vitro

Transport of Arylsulfatase A across the Blood-Brain Barrier in Vitro

Detouring of cisplatin to access mitochondrial genome for overcoming resistance

Lipoprotein Particles Cross the Blood–Brain Barrier inDrosophila

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