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

Autor:	Martin G. Pomper, Jan Gettemans, Miroslaw Janowski, Olivier Zwaenepoel, Wojciech G. Lesniak, Ala Lisok, Michał Zawadzki, Piotr Walczak, Babak Behnam Azad, Chengyan Chu, Anna Jablonska
Rok vydání:	2019
Předmět:	Dendrimers Biodistribution Bevacizumab medicine.drug_class Pharmacology Monoclonal antibody Article 030218 nuclear medicine & medical imaging Mice 03 medical and health sciences 0302 clinical medicine Positron Emission Tomography Computed Tomography Image Processing Computer-Assisted medicine Animals Tissue Distribution Radiology Nuclear Medicine and imaging Radioisotopes medicine.diagnostic_test Chemistry Immunogenicity Brain Arteries General Medicine Single-Domain Antibodies Deferoxamine Nylons Protein Transport Positron emission tomography 030220 oncology & carcinogenesis Zirconium Mannitol medicine.drug Conjugate
Zdroj:	Eur J Nucl Med Mol Imaging
ISSN:	1619-7089 1619-7070
DOI:	10.1007/s00259-019-04347-y
Popis:	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 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 substituted with butane-1,2-diol functionalities to generate G4(DFO)(3)(Bdiol)(110). Resulting conjugates were radiolabeled with (89)Zr. Brain uptake of (89)ZrNB(DFO)(2) and (89)ZrG4(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 PET over 30 min to assess brain uptake and clearance, followed by whole-body PET-CT imaging at 1h and 24h post-infusion (pi). Imaging results were subsequently validated by ex vivo biodistribution. RESULTS: Intravenous administration of (89)ZrNB(DFO)(2) and (89)ZrG4(DFO)(3)(Bdiol)(110) resulted in their negligible brain accumulation regardless of BBB status and timing of OBBBO. Intra-arterial (IA) administration of (89)ZrNB(DFO)(2) dramatically increased its brain uptake, which was further potentiated with prior OBBBO. Half of the initial brain uptake was retained after 24h. In contrast, IA infusion of (89)ZrNB(DFO)(3)(Bdiol)(110) resulted in poor initial accumulation in the brain with complete clearance within 1h 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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::72586df59b9a551b3ff6ba5468cf49e4 https://doi.org/10.1007/s00259-019-04347-y Zobrazit plný text záznamu Plný text ve formátu PDF Plný text ve formátu HTML
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