PET imaging of distinct brain uptake of a nanobody and similarly-sized PAMAM dendrimers after intra-arterial administration

Wojciech Lesniak, Chengyan Chu, Anna Jablonska, Babak Behnam Azad, Olivier Zwaenepoel, Michal Zawadzki, Ala Lisok, Martin Gilbert Pomper, Piotr Walczak, Jan Gettemans, Miroslaw Janowski

Research output: Contribution to journalArticle

Abstract

Introduction: We have recently shown that intracerebral delivery of an anti-VEGF monoclonal antibody bevacizumab using an intra-arterial (IA) infusion is more effective than intravenous administration. While antibodies are quickly emerging as therapeutics, their disadvantages such as large size, production logistics and immunogenicity motivate search for alternatives. Thus we have studied brain uptake of nanobodies and polyamidoamine (PAMAM) dendrimers. Methods: Nanobodies were conjugated with deferoxamine (DFO) to generate NB(DFO)2. Generation-4 PAMAM dendrimers were conjugated with DFO, and subsequently primary amines were capped with butane-1,2-diol functionalities to generate G4(DFO)3(Bdiol)110. Resulting conjugates were radiolabeled with zirconium-89. Brain uptake of 89ZrNB(DFO)2 and 89ZrG4(DFO)3(Bdiol)110 upon carotid artery vs tail vein infusions with intact BBB or osmotic blood–brain barrier opening (OBBBO) with mannitol in mice was monitored by dynamic positron emission tomography (PET) over 30 min to assess brain uptake and clearance, followed by whole-body PET-CT (computed tomography) imaging at 1 h and 24 h post-infusion (pi). Imaging results were subsequently validated by ex-vivo biodistribution. Results: Intravenous administration of 89ZrNB(DFO)2 and 89ZrG4(DFO)3(Bdiol)110 resulted in their negligible brain accumulation regardless of BBB status and timing of OBBBO. Intra-arterial (IA) administration of 89ZrNB(DFO)2 dramatically increased its brain uptake, which was further potentiated with prior OBBBO. Half of the initial brain uptake was retained after 24 h. In contrast, IA infusion of 89ZrG4(DFO)3(Bdiol)110 resulted in poor initial accumulation in the brain, with complete clearance within 1 h of administration. Ex-vivo biodistribution results reflected those on PET-CT. Conclusions: IA delivery of nanobodies might be an attractive therapeutic platform for CNS disorders where prolonged intracranial retention is necessary.

Original languageEnglish (US)
JournalEuropean Journal of Nuclear Medicine and Molecular Imaging
DOIs
StatePublished - Jan 1 2019

Fingerprint

Single-Domain Antibodies
Dendrimers
Deferoxamine
Neuroimaging
Positron-Emission Tomography
Brain
Intra Arterial Infusions
Intravenous Administration
Poly(amidoamine)
Brain Diseases
Mannitol
Carotid Arteries
Vascular Endothelial Growth Factor A
Amines
Tail
Veins

Keywords

  • Brain
  • Dendrimer
  • Intra-arterial
  • Nanobody
  • PET
  • Zirconium

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging

Cite this

@article{ff6dd6597aee49af862892d04405f975,
title = "PET imaging of distinct brain uptake of a nanobody and similarly-sized PAMAM dendrimers after intra-arterial administration",
abstract = "Introduction: We have recently shown that intracerebral delivery of an anti-VEGF monoclonal antibody bevacizumab using an intra-arterial (IA) infusion is more effective than intravenous administration. While antibodies are quickly emerging as therapeutics, their disadvantages such as large size, production logistics and immunogenicity motivate search for alternatives. Thus we have studied brain uptake of nanobodies and polyamidoamine (PAMAM) dendrimers. Methods: Nanobodies were conjugated with deferoxamine (DFO) to generate NB(DFO)2. Generation-4 PAMAM dendrimers were conjugated with DFO, and subsequently primary amines were capped with butane-1,2-diol functionalities to generate G4(DFO)3(Bdiol)110. Resulting conjugates were radiolabeled with zirconium-89. Brain uptake of 89ZrNB(DFO)2 and 89ZrG4(DFO)3(Bdiol)110 upon carotid artery vs tail vein infusions with intact BBB or osmotic blood–brain barrier opening (OBBBO) with mannitol in mice was monitored by dynamic positron emission tomography (PET) over 30 min to assess brain uptake and clearance, followed by whole-body PET-CT (computed tomography) imaging at 1 h and 24 h post-infusion (pi). Imaging results were subsequently validated by ex-vivo biodistribution. Results: Intravenous administration of 89ZrNB(DFO)2 and 89ZrG4(DFO)3(Bdiol)110 resulted in their negligible brain accumulation regardless of BBB status and timing of OBBBO. Intra-arterial (IA) administration of 89ZrNB(DFO)2 dramatically increased its brain uptake, which was further potentiated with prior OBBBO. Half of the initial brain uptake was retained after 24 h. In contrast, IA infusion of 89ZrG4(DFO)3(Bdiol)110 resulted in poor initial accumulation in the brain, with complete clearance within 1 h of administration. Ex-vivo biodistribution results reflected those on PET-CT. Conclusions: IA delivery of nanobodies might be an attractive therapeutic platform for CNS disorders where prolonged intracranial retention is necessary.",
keywords = "Brain, Dendrimer, Intra-arterial, Nanobody, PET, Zirconium",
author = "Wojciech Lesniak and Chengyan Chu and Anna Jablonska and {Behnam Azad}, Babak and Olivier Zwaenepoel and Michal Zawadzki and Ala Lisok and Pomper, {Martin Gilbert} and Piotr Walczak and Jan Gettemans and Miroslaw Janowski",
year = "2019",
month = "1",
day = "1",
doi = "10.1007/s00259-019-04347-y",
language = "English (US)",
journal = "European Journal of Nuclear Medicine and Molecular Imaging",
issn = "1619-7070",
publisher = "Springer Verlag",

}

TY - JOUR

T1 - PET imaging of distinct brain uptake of a nanobody and similarly-sized PAMAM dendrimers after intra-arterial administration

AU - Lesniak, Wojciech

AU - Chu, Chengyan

AU - Jablonska, Anna

AU - Behnam Azad, Babak

AU - Zwaenepoel, Olivier

AU - Zawadzki, Michal

AU - Lisok, Ala

AU - Pomper, Martin Gilbert

AU - Walczak, Piotr

AU - Gettemans, Jan

AU - Janowski, Miroslaw

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Introduction: We have recently shown that intracerebral delivery of an anti-VEGF monoclonal antibody bevacizumab using an intra-arterial (IA) infusion is more effective than intravenous administration. While antibodies are quickly emerging as therapeutics, their disadvantages such as large size, production logistics and immunogenicity motivate search for alternatives. Thus we have studied brain uptake of nanobodies and polyamidoamine (PAMAM) dendrimers. Methods: Nanobodies were conjugated with deferoxamine (DFO) to generate NB(DFO)2. Generation-4 PAMAM dendrimers were conjugated with DFO, and subsequently primary amines were capped with butane-1,2-diol functionalities to generate G4(DFO)3(Bdiol)110. Resulting conjugates were radiolabeled with zirconium-89. Brain uptake of 89ZrNB(DFO)2 and 89ZrG4(DFO)3(Bdiol)110 upon carotid artery vs tail vein infusions with intact BBB or osmotic blood–brain barrier opening (OBBBO) with mannitol in mice was monitored by dynamic positron emission tomography (PET) over 30 min to assess brain uptake and clearance, followed by whole-body PET-CT (computed tomography) imaging at 1 h and 24 h post-infusion (pi). Imaging results were subsequently validated by ex-vivo biodistribution. Results: Intravenous administration of 89ZrNB(DFO)2 and 89ZrG4(DFO)3(Bdiol)110 resulted in their negligible brain accumulation regardless of BBB status and timing of OBBBO. Intra-arterial (IA) administration of 89ZrNB(DFO)2 dramatically increased its brain uptake, which was further potentiated with prior OBBBO. Half of the initial brain uptake was retained after 24 h. In contrast, IA infusion of 89ZrG4(DFO)3(Bdiol)110 resulted in poor initial accumulation in the brain, with complete clearance within 1 h of administration. Ex-vivo biodistribution results reflected those on PET-CT. Conclusions: IA delivery of nanobodies might be an attractive therapeutic platform for CNS disorders where prolonged intracranial retention is necessary.

AB - Introduction: We have recently shown that intracerebral delivery of an anti-VEGF monoclonal antibody bevacizumab using an intra-arterial (IA) infusion is more effective than intravenous administration. While antibodies are quickly emerging as therapeutics, their disadvantages such as large size, production logistics and immunogenicity motivate search for alternatives. Thus we have studied brain uptake of nanobodies and polyamidoamine (PAMAM) dendrimers. Methods: Nanobodies were conjugated with deferoxamine (DFO) to generate NB(DFO)2. Generation-4 PAMAM dendrimers were conjugated with DFO, and subsequently primary amines were capped with butane-1,2-diol functionalities to generate G4(DFO)3(Bdiol)110. Resulting conjugates were radiolabeled with zirconium-89. Brain uptake of 89ZrNB(DFO)2 and 89ZrG4(DFO)3(Bdiol)110 upon carotid artery vs tail vein infusions with intact BBB or osmotic blood–brain barrier opening (OBBBO) with mannitol in mice was monitored by dynamic positron emission tomography (PET) over 30 min to assess brain uptake and clearance, followed by whole-body PET-CT (computed tomography) imaging at 1 h and 24 h post-infusion (pi). Imaging results were subsequently validated by ex-vivo biodistribution. Results: Intravenous administration of 89ZrNB(DFO)2 and 89ZrG4(DFO)3(Bdiol)110 resulted in their negligible brain accumulation regardless of BBB status and timing of OBBBO. Intra-arterial (IA) administration of 89ZrNB(DFO)2 dramatically increased its brain uptake, which was further potentiated with prior OBBBO. Half of the initial brain uptake was retained after 24 h. In contrast, IA infusion of 89ZrG4(DFO)3(Bdiol)110 resulted in poor initial accumulation in the brain, with complete clearance within 1 h of administration. Ex-vivo biodistribution results reflected those on PET-CT. Conclusions: IA delivery of nanobodies might be an attractive therapeutic platform for CNS disorders where prolonged intracranial retention is necessary.

KW - Brain

KW - Dendrimer

KW - Intra-arterial

KW - Nanobody

KW - PET

KW - Zirconium

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U2 - 10.1007/s00259-019-04347-y

DO - 10.1007/s00259-019-04347-y

M3 - Article

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JO - European Journal of Nuclear Medicine and Molecular Imaging

JF - European Journal of Nuclear Medicine and Molecular Imaging

SN - 1619-7070

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