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

Jeroen A C M Goos; Maria Davydova; Thomas R. Dilling; Andrew Cho; Mike A. Cornejo; Abhishek Gupta; William S. Price; Simon Puttick; Michael R. Whittaker; John F. Quinn; Thomas P. Davis; Jason S. Lewis

doi:10.1016/j.nucmedbio.2020.02.012

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

Jeroen A C M Goos, Maria Davydova, Thomas R. Dilling, Andrew Cho, Mike A. Cornejo, Abhishek Gupta, William S. Price, Simon Puttick, Michael R. Whittaker, John F. Quinn, Thomas P. Davis, Jason S. Lewis

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Research output: Contribution to journal › Article › Research › peer-review

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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.

Original language	English
Pages (from-to)	63-72
Number of pages	10
Journal	Nuclear Medicine and Biology
Volume	84-85
DOIs	https://doi.org/10.1016/j.nucmedbio.2020.02.012
Publication status	Published - 1 May 2020

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

EPR effect
Nanoparticle
PET
Pretargeting
Star polymer

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10.1016/j.nucmedbio.2020.02.012

Cite this

@article{762822ee6678462ca264bb54621b7929,

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.",

keywords = "EPR effect, Nanoparticle, PET, Pretargeting, Star polymer",

author = "Goos, \{Jeroen A C M\} and Maria Davydova and Dilling, \{Thomas R.\} and Andrew Cho and Cornejo, \{Mike A.\} and Abhishek Gupta and Price, \{William S.\} and Simon Puttick and Whittaker, \{Michael R.\} and Quinn, \{John F.\} and Davis, \{Thomas P.\} and Lewis, \{Jason S.\}",

year = "2020",

month = may,

day = "1",

doi = "10.1016/j.nucmedbio.2020.02.012",

language = "English",

volume = "84-85",

pages = "63--72",

journal = "Nuclear Medicine and Biology",

issn = "0969-8051",

publisher = "Elsevier",

}

TY - JOUR

T1 - Design and preclinical evaluation of nanostars for the passive pretargeting of tumor tissue

AU - Goos, Jeroen A C M

AU - Davydova, Maria

AU - Dilling, Thomas R.

AU - Cho, Andrew

AU - Cornejo, Mike A.

AU - Gupta, Abhishek

AU - Price, William S.

AU - Puttick, Simon

AU - Whittaker, Michael R.

AU - Quinn, John F.

AU - Davis, Thomas P.

AU - Lewis, Jason S.

PY - 2020/5/1

Y1 - 2020/5/1

N2 - 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.

AB - 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.

KW - EPR effect

KW - Nanoparticle

KW - PET

KW - Pretargeting

KW - Star polymer

UR - https://www.scopus.com/pages/publications/85080075634

U2 - 10.1016/j.nucmedbio.2020.02.012

DO - 10.1016/j.nucmedbio.2020.02.012

M3 - Article

AN - SCOPUS:85080075634

SN - 0969-8051

VL - 84-85

SP - 63

EP - 72

JO - Nuclear Medicine and Biology

JF - Nuclear Medicine and Biology

ER -

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

Abstract

UN SDGs

Keywords

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ARC Centre of Excellence in Convergent Bio-Nano Science and Technology

Cite this

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

Abstract

UN SDGs

Keywords

Access to Document

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Projects

ARC Centre of Excellence in Convergent Bio-Nano Science and Technology

Cite this