The synergistic effect of chlorotoxin-mApoE in boosting drug-loaded liposomes across the BBB

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Abstract

We designed liposomes dually functionalized with ApoE-derived peptide (mApoE) and chlorotoxin (ClTx) to improve their blood–brain barrier (BBB) crossing. Our results demonstrated the synergistic activity of ClTx-mApoE in boosting doxorubicin-loaded liposomes across the BBB, keeping the anti-tumour activity of the drug loaded: mApoE acts promoting cellular uptake, while ClTx promotes exocytosis of liposomes.

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Most cited references 22

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Intracellular transport and regulation of transcytosis across the blood–brain barrier

Roberto Villaseñor, Josephine Lampe, Markus Schwaninger … (2018)

The blood–brain barrier is a dynamic multicellular interface that regulates the transport of molecules between the blood circulation and the brain parenchyma. Proteins and peptides required for brain homeostasis cross the blood–brain barrier via transcellular transport, but the mechanisms that control this pathway are not well characterized. Here, we highlight recent studies on intracellular transport and transcytosis across the blood–brain barrier. Endothelial cells at the blood–brain barrier possess an intricate endosomal network that allows sorting to diverse cellular destinations. Internalization from the plasma membrane, endosomal sorting, and exocytosis all contribute to the regulation of transcytosis. Transmembrane receptors and blood-borne proteins utilize different pathways and mechanisms for transport across brain endothelial cells. Alterations to intracellular transport in brain endothelial cells during diseases of the central nervous system contribute to blood–brain barrier disruption and disease progression. Harnessing the intracellular sorting mechanisms at the blood–brain barrier can help improve delivery of biotherapeutics to the brain.

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Pharmacokinetics, Brain Delivery, and Efficacy in Brain Tumor-Bearing Mice of Glutathione Pegylated Liposomal Doxorubicin (2B3-101)

Pieter J Gaillard, Chantal C M Appeldoorn, Rick Dorland … (2014)

Brain cancer is a devastating disease affecting many people worldwide. Effective treatment with chemotherapeutics is limited due to the presence of the blood-brain barrier (BBB) that tightly regulates the diffusion of endogenous molecules but also xenobiotics. Glutathione pegylated liposomal doxorubicin (2B3-101) is being developed as a new treatment option for patients with brain cancer. It is based on already marketed pegylated liposomal doxorubicin (Doxil®/Caelyx®), with an additional glutathione coating that safely enhances drug delivery across the BBB. Uptake of 2B3-101 by human brain capillary endothelial cells in vitro was time-, concentration- and temperature-dependent, while pegylated liposomal doxorubicin mainly remained bound to the cells. In vivo, 2B3-101 and pegylated liposomal doxorubicin had a comparable plasma exposure in mice, yet brain retention 4 days after administration was higher for 2B3-101. 2B3-101 was overall well tolerated by athymic FVB mice with experimental human glioblastoma (luciferase transfected U87MG). In 2 independent experiments a strong inhibition of brain tumor growth was observed for 2B3-101 as measured by bioluminescence intensity. The effect of weekly administration of 5 mg/kg 2B3-101 was more pronounced compared to pegylated liposomal doxorubicin (p<0.05) and saline (p<0.01). Two out of 9 animals receiving 2B3-101 showed a complete tumor regression. Twice-weekly injections of 5 mg/kg 2B3-101 again had a significant effect in inhibiting brain tumor growth (p<0.001) compared to pegylated liposomal doxorubicin and saline, and a complete regression was observed in 1 animal treated with 2B3-101. In addition, twice-weekly dosing of 2B3-101 significantly increased the median survival time by 38.5% (p<0.001) and 16.1% (p<0.05) compared to saline and pegylated liposomal doxorubicin, respectively. Overall, these data demonstrate that glutathione pegylated liposomal doxorubicin enhances the effective delivery of doxorubicin to brain tumors and could become a promising new therapeutic option for the treatment of brain malignancies.

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Purification and characterization of chlorotoxin, a chloride channel ligand from the venom of the scorpion.

J DeBin, J E Maggio, G Strichartz (1993)

We have previously demonstrated that the venom of the scorpion Leiurus quinquestriatus blocks small-conductance Cl- channels, derived from epithelial cells, when applied to the cytoplasmic surface. We have now purified to near homogeneity, and characterized, the component responsible for this blocking activity. It is a small basic peptide of 4,070 Da. The primary amino acid structure shows considerable homology to a class of previously described putative short insectotoxins. A brief characterization of the kinetics of Cl- channel block as well as a demonstration of toxicity to arthropods is also presented.

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Author and article information

Contributors

Beatrice Formicola: b.formicola@campus.unimib.it

Journal

Journal ID (nlm-ta): J Nanobiotechnology

Journal ID (iso-abbrev): J Nanobiotechnology

Title: Journal of Nanobiotechnology

Publisher: BioMed Central (London )

ISSN (Electronic): 1477-3155

Publication date (Electronic): 11 November 2019

Publication date PMC-release: 11 November 2019

Publication date Collection: 2019

Volume: 17

Electronic Location Identifier: 115

Affiliations

[1 ]ISNI 0000 0001 2174 1754, GRID grid.7563.7, School of Medicine and Surgery, , University of Milano-Bicocca, ; Via Raoul Follereau 3, 20854 Vedano al Lambro, MB Italy

[2 ]ISNI 0000 0001 2167 7588, GRID grid.11749.3a, Department of Drug Delivery, , Helmholtz Institute for Pharmaceutical Research Saarland, Saarland University, ; 66123 Saarbrücken, Germany

[3 ]ISNI 0000 0004 0548 6732, GRID grid.425202.3, Leibniz Institute for New Materials, ; Campus D2 2, 66123 Saarbrücken, Germany

[4 ]ISNI 0000 0001 2174 1754, GRID grid.7563.7, Bio Organic Chemistry Laboratory, Department of Biotechnology and Biosciences, , University of Milano-Bicocca, ; Via Raoul Follereau 3, 20854 Vedano al Lambro, MB Italy

[5 ]ISNI 0000 0001 2203 2861, GRID grid.29078.34, Istituto Dalle Molle di Studi Sull’Intelligenza Artificiale (IDSIA), Scuola Universitaria Professionale Della Svizzera Italiana (SUPSI), , Università Della Svizzera Italiana (USI), ; Manno, Switzerland

[6 ]ISNI 0000 0004 1937 0343, GRID grid.4800.c, Department of Mechanical and Aerospace Engineering (DIMEAS), , Politecnico di Torino, ; Corso Duca degli Abruzzi 24, 10128 Turin, Italy

[7 ]ISNI 0000 0004 0643 431X, GRID grid.462098.1, U1016, Institut Cochin, Inserm, ; Paris, France

Article

Publisher ID: 546

DOI: 10.1186/s12951-019-0546-3

PMC ID: 6844026

PubMed ID: 31711496

SO-VID: b5240254-e66f-4ded-9c85-3dae430988dc

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 2 September 2019

Date accepted : 27 October 2019

Funding

Funded by: JPND

Award ID: JPND-COFUND_FP-829-031 (2016-2019)

Award Recipient : Francesca Re

Funded by: H2020-MSCA-ITN-2014

Award ID: 642028

Award Recipient : Laura Russo

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ScienceOpen disciplines: Biotechnology

Keywords: nanoparticles,liposomes,brain,blood–brain barrier,drug delivery,doxorubicin,chlorotoxin,glioblastoma

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ScienceOpen disciplines: Biotechnology

Keywords: nanoparticles, liposomes, brain, blood–brain barrier, drug delivery, doxorubicin, chlorotoxin, glioblastoma

The synergistic effect of chlorotoxin-mApoE in boosting drug-loaded liposomes across the BBB

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Abstract

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Nanoparticles to cross the blood-brain barrier (BBB)

Most cited references 22

Intracellular transport and regulation of transcytosis across the blood–brain barrier

Pharmacokinetics, Brain Delivery, and Efficacy in Brain Tumor-Bearing Mice of Glutathione Pegylated Liposomal Doxorubicin (2B3-101)

Purification and characterization of chlorotoxin, a chloride channel ligand from the venom of the scorpion.

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