Design and preclinical evaluation of nanostars for the passive pretargeting of tumor tissue Journal Article


Authors: Goos, J. A. C. M.; Davydova, M.; Dilling, T. R.; Cho, A.; Cornejo, M. A.; Gupta, A.; Price, W. S.; Puttick, S.; Whittaker, M. R.; Quinn, J. F.; Davis, T. P.; Lewis, J. S.
Article Title: Design and preclinical evaluation of nanostars for the passive pretargeting of tumor tissue
Abstract: Introduction: Pretargeting strategies that do not rely on the expression of molecular targets have expanded imaging and therapy options for cancer patients. Nanostars with designed multivalency and which highly accumulate in tumor tissue via the enhanced permeability and retention (EPR) effect may therefore be the ideal vectors for the development of a passive pretargeting approach. Methods: Nanostars were synthesized, consisting of 7–8 center-cross-linked arms that were modified with trans-cyclooctene (TCO) using poly(ethylene glycol) (PEG) linkers of 12 or 106 monomer units or without linker. The bioorthogonal click reaction with radiofluorinated 2,2′-(7-(2-(tetrazine-poly(ethyleneglycol)11-amino)-2-oxoethyl)-1,4,7-triazonane-1,4-diyl)diacetic acid ([18F]F-Tz-PEG11-NODA) or 2,2′-(7-(2-(tetrazine-amino)-2-oxoethyl)-1,4,7-triazonane-1,4-diyl)diacetic acid ([18F]F-Tz-NODA) was measured by ex vivo biodistribution studies and positron emission tomography (PET) in mice bearing tumors with high EPR characteristics. Bioorthogonal masking was performed using a tetrazine-functionalized dextran polymer (Tz-DP). Results: Highest tumor accumulation of [18F]F-Tz-PEG11-NODA was observed for nanostars functionalized with TCO without linker, with a tumor uptake of 3.2 ± 0.4%ID/g and a tumor-to-muscle ratio of 12.8 ± 4.2, tumor-to-large intestine ratio of 0.5 ± 0.3 and tumor-to-kidney ratio of 2.0 ± 0.3, being significantly higher than for nanostars functionalized with TCO-PEG12 (P < 0.05) or TCO-PEG106 (P < 0.05). Tumor uptake and tumor-to-tissue ratios did not improve upon bioorthogonal masking with Tz-DP or when using a smaller, more lipophilic tetrazine([18F]F-Tz-NODA). Conclusions: A pretargeting strategy was developed based on the passive delivery of TCO-functionalized nanostars. Such a strategy would allow for the imaging and treatment of tumors with apparent EPR characteristics, with high radioactive tumor doses and minimal doses to off-target tissues. © 2020
Keywords: controlled study; unclassified drug; nonhuman; positron emission tomography; mouse; animal tissue; animal experiment; in vitro study; drug design; drug synthesis; dextran; kidney; drug accumulation; drug distribution; radiopharmaceutical agent; drug tissue level; nanoparticle; high performance liquid chromatography; ex vivo study; pet; intestine; diels alder reaction; macrogol; lipophilicity; proton nuclear magnetic resonance; muscle; cycloalkene; cross linking; electron spin resonance; fluorination; pretargeting; transcyclooctene; female; article; epr effect; star polymer; 2,2' [7 [2 (tetrazine amino) 2 oxoethyl] 1,4,7 triazonane 1,4 diyl]diacetic acid f 18; 2,2' [7 [2 [tetrazine poly(ethyleneglycol)amino] 2 oxoethyl] 1,4,7 triazonane 1,4 diyl]diacetic acid f 18; nanostar; bioorthogonal inverse electron demand diels alder click reaction; radiofluorination
Journal Title: Nuclear Medicine and Biology
Volume: 84-85
ISSN: 0969-8051
Publisher: Elsevier Science Inc.  
Date Published: 2020-05-01
Start Page: 63
End Page: 72
Language: English
DOI: 10.1016/j.nucmedbio.2020.02.012
PROVIDER: scopus
PUBMED: 32135473
PMCID: PMC7253331
DOI/URL:
Notes: Article -- Export Date: 1 April 2020 -- Source: Scopus
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MSK Authors
  1. Jason S Lewis
    365 Lewis
  2. Thomas R Dilling
    10 Dilling
  3. Jeroen Adrianus Cornelis Maria Goos
    5 Goos