Open AccessDual-Modality PET–SPECT Image-Guided Pretargeting Delivery in HER2(+) Breast Cancer Models
Author(s) -
Sudath Hapuarachchige,
Ge Si,
Colin T. Huang,
Wojciech G. Lesniak,
Ronnie C. Mease,
Xin Guo,
Kathleen Gabrielson,
Dmitri Artemov
Publication year - 2021
Publication title -
biomacromolecules
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.689
H-Index - 220
eISSN - 1526-4602
pISSN - 1525-7797
DOI - 10.1021/acs.biomac.1c00918
Subject(s) - pretargeting , biodistribution , bioorthogonal chemistry , drug delivery , in vivo , chemistry , cancer , ex vivo , breast cancer , positron emission tomography , pharmacology , medicine , nuclear medicine , cancer research , in vitro , radioimmunotherapy , immunology , biochemistry , click chemistry , combinatorial chemistry , monoclonal antibody , antibody , microbiology and biotechnology , organic chemistry , biology
Pretargeted drug delivery has been explored for decades as a promising approach in cancer therapy. An image-guided pretargeting strategy significantly enhances the intrinsic advantages of this approach since imaging the pretargeting step can be used for diagnostic purposes, while imaging of the drug delivery step can be utilized to evaluate drug distribution and assess therapeutic response. A trastuzumab (Tz)-based HER2 pretargeting component (Tz-TCO-[ 89 Zr-DFO]) was developed by conjugating with trans -cyclooctene (TCO) bioorthogonal click chemistry functional groups and deferoxamine (DFO) to enable radiolabeling with a 89 Zr PET tracer. The drug delivery component (HSA-DM1-Tt-[ 99m Tc-HyNic]) was developed by conjugating human serum albumin (HSA) with mertansine (DM1), tetrazine (Tt) functional groups, and a HyNic chelator and radiolabeling with 99m Tc. For ex vivo biodistribution studies, pretargeting and delivery components (without drug) were administered subsequently to mice bearing human HER2(+) breast cancer xenografts, and a high tumor uptake of Tz-TCO-[ 89 Zr-DFO] (26.4% ID/g) and HSA-Tt-[ 99m Tc-HyNic] (4.6% ID/g) was detected at 24 h postinjection. In vivo treatment studies were performed in the same HER2(+) breast cancer model using PET-SPECT image guidance. The increased tumor uptake of the pretargeting and drug delivery components was detected by PET-CT and SPECT-CT, respectively. The study showed a significant 92% reduction of the relative tumor volume in treated mice (RTV = 0.08 in 26 days), compared to the untreated control mice (RTV = 1.78 in 11 days) and to mice treated with only HSA-DM1-Tt-[ 99m Tc-HyNic] (RTV = 1.88 in 16 days). Multimodality PET-SPECT image-guided and pretargeted drug delivery can be utilized to maximize efficacy, predict therapeutic response, and minimize systemic toxicity.