Trans-Cyclooctene-Functionalized PeptoBrushes with Improved Reaction Kinetics of the Tetrazine Ligation for Pretargeted Nuclear Imaging

E Johanna L Stéen; Jesper T Jørgensen; Kerstin Johann; Kamilla Norregaard; Barbara Sohr; Dennis Svatunek; Alexander Birke; Vladimir Shalgunov; Patricia E Edem; Raffaella Rossin; Christine Seidl; Friederike Schmid; Marc S Robillard; Jesper L Kristensen; Hannes Mikula; Matthias Barz; Andreas Kjaer; Matthias M Herth

doi:10.1021/acsnano.9b06905

Trans-Cyclooctene-Functionalized PeptoBrushes with Improved Reaction Kinetics of the Tetrazine Ligation for Pretargeted Nuclear Imaging

E Johanna L Stéen, Jesper T Jørgensen, Kerstin Johann, Kamilla Norregaard, Barbara Sohr, Dennis Svatunek, Alexander Birke, Vladimir Shalgunov, Patricia E Edem, Raffaella Rossin, Christine Seidl, Friederike Schmid, Marc S Robillard, Jesper L Kristensen, Hannes Mikula, Matthias Barz, Andreas Kjaer, Matthias M Herth

11 Citations (Scopus)

Abstract

Tumor targeting using agents with slow pharmacokinetics represents a major challenge in nuclear imaging and targeted radionuclide therapy as they most often result in low imaging contrast and high radiation dose to healthy tissue. To address this challenge, we developed a polymer-based targeting agent that can be used for pretargeted imaging and thus separates tumor accumulation from the imaging step in time. The developed targeting agent is based on polypeptide-graft-polypeptoid polymers (PeptoBrushes) functionalized with trans-cyclooctene (TCO). The complementary ¹¹¹In-labeled imaging agent is a 1,2,4,5-tetrazine derivative, which can react with aforementioned TCO-modified PeptoBrushes in a rapid bioorthogonal ligation. A high degree of TCO loading (up to 30%) was achieved, without altering the physicochemical properties of the polymeric nanoparticle. The highest degree of TCO loading resulted in significantly increased reaction rates (77-fold enhancement) compared to those with small molecule TCO moieties when using lipophilic tetrazines. Based on computer simulations, we hypothesize that this increase is a result of hydrophobic effects and significant rearrangements within the polymer framework, in which hydrophobic patches of TCO moieties are formed. These patches attract lipophilic tetrazines, leading to increased reaction rates in the bioorthogonal ligation. The most reactive system was evaluated as a targeting agent for pretargeted imaging in tumor-bearing mice. After the setup was optimized, sufficient tumor-to-background ratios were achieved as early as 2 h after administration of the tetrazine imaging agent, which further improved at 22 h, enabling clear visualization of CT-26 tumors. These findings show the potential of PeptoBrushes to be used as a pretargeting agent when an optimized dose of polymer is used.

Original language	English
Journal	ACS Nano
ISSN	1936-0851
DOIs	https://doi.org/10.1021/acsnano.9b06905
Publication status	Published - 28 Jan 2020

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Stéen, E. J. L., Jørgensen, J. T., Johann, K., Norregaard, K., Sohr, B., Svatunek, D., Birke, A., Shalgunov, V., Edem, P. E., Rossin, R., Seidl, C., Schmid, F., Robillard, M. S., Kristensen, J. L., Mikula, H., Barz, M., Kjaer, A., & Herth, M. M. (2020). Trans-Cyclooctene-Functionalized PeptoBrushes with Improved Reaction Kinetics of the Tetrazine Ligation for Pretargeted Nuclear Imaging. ACS Nano. https://doi.org/10.1021/acsnano.9b06905

Stéen, EJL, Jørgensen, JT, Johann, K, Norregaard, K, Sohr, B, Svatunek, D, Birke, A, Shalgunov, V, Edem, PE, Rossin, R, Seidl, C, Schmid, F, Robillard, MS, Kristensen, JL, Mikula, H, Barz, M, Kjaer, A & Herth, MM 2020, 'Trans-Cyclooctene-Functionalized PeptoBrushes with Improved Reaction Kinetics of the Tetrazine Ligation for Pretargeted Nuclear Imaging', ACS Nano. https://doi.org/10.1021/acsnano.9b06905

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title = "Trans-Cyclooctene-Functionalized PeptoBrushes with Improved Reaction Kinetics of the Tetrazine Ligation for Pretargeted Nuclear Imaging",

abstract = "Tumor targeting using agents with slow pharmacokinetics represents a major challenge in nuclear imaging and targeted radionuclide therapy as they most often result in low imaging contrast and high radiation dose to healthy tissue. To address this challenge, we developed a polymer-based targeting agent that can be used for pretargeted imaging and thus separates tumor accumulation from the imaging step in time. The developed targeting agent is based on polypeptide-graft-polypeptoid polymers (PeptoBrushes) functionalized with trans-cyclooctene (TCO). The complementary 111In-labeled imaging agent is a 1,2,4,5-tetrazine derivative, which can react with aforementioned TCO-modified PeptoBrushes in a rapid bioorthogonal ligation. A high degree of TCO loading (up to 30%) was achieved, without altering the physicochemical properties of the polymeric nanoparticle. The highest degree of TCO loading resulted in significantly increased reaction rates (77-fold enhancement) compared to those with small molecule TCO moieties when using lipophilic tetrazines. Based on computer simulations, we hypothesize that this increase is a result of hydrophobic effects and significant rearrangements within the polymer framework, in which hydrophobic patches of TCO moieties are formed. These patches attract lipophilic tetrazines, leading to increased reaction rates in the bioorthogonal ligation. The most reactive system was evaluated as a targeting agent for pretargeted imaging in tumor-bearing mice. After the setup was optimized, sufficient tumor-to-background ratios were achieved as early as 2 h after administration of the tetrazine imaging agent, which further improved at 22 h, enabling clear visualization of CT-26 tumors. These findings show the potential of PeptoBrushes to be used as a pretargeting agent when an optimized dose of polymer is used.",

author = "St{\'e}en, {E Johanna L} and J{\o}rgensen, {Jesper T} and Kerstin Johann and Kamilla Norregaard and Barbara Sohr and Dennis Svatunek and Alexander Birke and Vladimir Shalgunov and Edem, {Patricia E} and Raffaella Rossin and Christine Seidl and Friederike Schmid and Robillard, {Marc S} and Kristensen, {Jesper L} and Hannes Mikula and Matthias Barz and Andreas Kjaer and Herth, {Matthias M}",

year = "2020",

month = jan,

day = "28",

doi = "10.1021/acsnano.9b06905",

language = "English",

journal = "ACS Nano",

issn = "1936-0851",

publisher = "American Chemical Society",

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TY - JOUR

T1 - Trans-Cyclooctene-Functionalized PeptoBrushes with Improved Reaction Kinetics of the Tetrazine Ligation for Pretargeted Nuclear Imaging

AU - Stéen, E Johanna L

AU - Jørgensen, Jesper T

AU - Johann, Kerstin

AU - Norregaard, Kamilla

AU - Sohr, Barbara

AU - Svatunek, Dennis

AU - Birke, Alexander

AU - Shalgunov, Vladimir

AU - Edem, Patricia E

AU - Rossin, Raffaella

AU - Seidl, Christine

AU - Schmid, Friederike

AU - Robillard, Marc S

AU - Kristensen, Jesper L

AU - Mikula, Hannes

AU - Barz, Matthias

AU - Kjaer, Andreas

AU - Herth, Matthias M

PY - 2020/1/28

Y1 - 2020/1/28

N2 - Tumor targeting using agents with slow pharmacokinetics represents a major challenge in nuclear imaging and targeted radionuclide therapy as they most often result in low imaging contrast and high radiation dose to healthy tissue. To address this challenge, we developed a polymer-based targeting agent that can be used for pretargeted imaging and thus separates tumor accumulation from the imaging step in time. The developed targeting agent is based on polypeptide-graft-polypeptoid polymers (PeptoBrushes) functionalized with trans-cyclooctene (TCO). The complementary 111In-labeled imaging agent is a 1,2,4,5-tetrazine derivative, which can react with aforementioned TCO-modified PeptoBrushes in a rapid bioorthogonal ligation. A high degree of TCO loading (up to 30%) was achieved, without altering the physicochemical properties of the polymeric nanoparticle. The highest degree of TCO loading resulted in significantly increased reaction rates (77-fold enhancement) compared to those with small molecule TCO moieties when using lipophilic tetrazines. Based on computer simulations, we hypothesize that this increase is a result of hydrophobic effects and significant rearrangements within the polymer framework, in which hydrophobic patches of TCO moieties are formed. These patches attract lipophilic tetrazines, leading to increased reaction rates in the bioorthogonal ligation. The most reactive system was evaluated as a targeting agent for pretargeted imaging in tumor-bearing mice. After the setup was optimized, sufficient tumor-to-background ratios were achieved as early as 2 h after administration of the tetrazine imaging agent, which further improved at 22 h, enabling clear visualization of CT-26 tumors. These findings show the potential of PeptoBrushes to be used as a pretargeting agent when an optimized dose of polymer is used.

AB - Tumor targeting using agents with slow pharmacokinetics represents a major challenge in nuclear imaging and targeted radionuclide therapy as they most often result in low imaging contrast and high radiation dose to healthy tissue. To address this challenge, we developed a polymer-based targeting agent that can be used for pretargeted imaging and thus separates tumor accumulation from the imaging step in time. The developed targeting agent is based on polypeptide-graft-polypeptoid polymers (PeptoBrushes) functionalized with trans-cyclooctene (TCO). The complementary 111In-labeled imaging agent is a 1,2,4,5-tetrazine derivative, which can react with aforementioned TCO-modified PeptoBrushes in a rapid bioorthogonal ligation. A high degree of TCO loading (up to 30%) was achieved, without altering the physicochemical properties of the polymeric nanoparticle. The highest degree of TCO loading resulted in significantly increased reaction rates (77-fold enhancement) compared to those with small molecule TCO moieties when using lipophilic tetrazines. Based on computer simulations, we hypothesize that this increase is a result of hydrophobic effects and significant rearrangements within the polymer framework, in which hydrophobic patches of TCO moieties are formed. These patches attract lipophilic tetrazines, leading to increased reaction rates in the bioorthogonal ligation. The most reactive system was evaluated as a targeting agent for pretargeted imaging in tumor-bearing mice. After the setup was optimized, sufficient tumor-to-background ratios were achieved as early as 2 h after administration of the tetrazine imaging agent, which further improved at 22 h, enabling clear visualization of CT-26 tumors. These findings show the potential of PeptoBrushes to be used as a pretargeting agent when an optimized dose of polymer is used.

U2 - 10.1021/acsnano.9b06905

DO - 10.1021/acsnano.9b06905

M3 - Journal article

C2 - 31820928

SN - 1936-0851

JO - ACS Nano

JF - ACS Nano

ER -

Trans-Cyclooctene-Functionalized PeptoBrushes with Improved Reaction Kinetics of the Tetrazine Ligation for Pretargeted Nuclear Imaging

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