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Imaging doxorubicin and polymer-drug conjugates of doxorubicin-induced cardiotoxicity with bispecific anti-myosin-anti-DTPA antibody and Tc-99m-labeled polymers

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Journal of Nuclear Cardiology Aims and scope

Abstract

Background

Radiolabeled anti-myosin imaging is well-established for imaging doxorubicin-induced cardiotoxicity. However, to enable imaging of drug-induced cardiotoxicity in small experimental animals, pretargeting with bispecific anti-myosin-anti-DTPA-Fab-Fab’ and targeting with high-specific radioactivity Tc-99m-DTPA-succinylated-polylysine (DSPL) was developed.

Methods

Mice were injected biweekly with 10 mg/kg Dox or its equivalent as D-Dox-PGA. Tc-99m-DSPL myocardial activity after pretargeting with bsAb-Fab-Fab’ was determined after gamma imaging performed at day 7 for Dox-treated mice and day 39 for all others.

Results

Mice treated with 10 mg/kg Dox lost 10% total body weight in 1 week and 20% after a second dose. Pretargeted mice treated with 30 mg/kg cumulative D-Dox-PGA dose showed no loss of body weight for the duration of the study. Cardiotoxicity was confirmed by gamma imaging and scintillation counting (1.9 ± 0.25 [mean% ID/g ± SD]) after 1 dose of Dox. Mice injected with 3 × 10 mg/kg Dox equivalent as D-Dox-PGA (0.4 ± 0.04, P < .01) and untreated 2 control groups (0.20 ± 0.05 and 0.19 ± 0.04, P < .01) showed significantly lower myocardial anti-myosin radioactivity relative to the 10 mg/kg Dox group.

Conclusion

Pretargeting with bsAb-Fab-Fab’ and targeting with Tc-99m labeled high-specific activity polymers enabled early visualization of doxorubicin induce cardiotoxicity in mice. Tolerated dose of D-Dox-PGA was greater than to 30 mg/kg Dox-equivalent dose with minimal cardiotoxicity.

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Abbreviations

Dox:

Doxorubicin

DTPA:

Diethylene triamine penta acetic acid

PGA:

Polyglutamic acid

DSPL:

DTPA-modified succinylated polylysine

D-Dox:

DTPA and doxorubicin-conjugated

FITC:

Fluorescein isothiocyanate

MTD:

Maximum tolerated dose

MAb:

Monoclonal antibody

bsAb:

Bispecific antibody

TNBS:

Trinitrobenzene sulfonic acid

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Acknowledgements

The prototype gamma camera was provided by Andrew Weisenberger from the Jefferson National Acclerator Faciities.

Disclosure

B.A. Khaw is a co-founder of Akrivis Technologies LLC. There is no conflict of interest with regards to the work of this research for any of the authors (Rajiv Panwar, Prashant Bhattarai, Vishwesh Patil, Keyur Gada, Stan Majewski, and Ban An Khaw).

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, Northeastern University, Boston, MA, 02115, USA

    Rajiv Panwar PhD, Prashant Bhattarai MS, Vishwesh Patil PhD, Keyur Gada PhD & Ban An Khaw PhD

  2. University of Virginia, Charlottesville, VA, USA

    Stan Majewski PhD

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  1. Rajiv Panwar PhD
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Correspondence to Ban An Khaw PhD.

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This work was supported by an unrestricted grant of the corresponding author from Gwathmey Inc., LLC, Cambridge, MA.

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Panwar, R., Bhattarai, P., Patil, V. et al. Imaging doxorubicin and polymer-drug conjugates of doxorubicin-induced cardiotoxicity with bispecific anti-myosin-anti-DTPA antibody and Tc-99m-labeled polymers. J. Nucl. Cardiol. 26, 1327–1344 (2019). https://doi.org/10.1007/s12350-018-1190-2

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