TY - JOUR
T1 - Recyclable cell-surface chemical tags for repetitive cancer targeting
AU - Bhatta, Rimsha
AU - Han, Joonsu
AU - Zhou, Jingyi
AU - Li, Haoyu
AU - Wang, Hua
N1 - Funding Information:
The authors would like to acknowledge the financial support from NSF CAR DMR-2143673 and the start-up package from the Department of Materials Science and Engineering at the University of Illinois at Urbana-Champaign and the Cancer Center at Illinois.
Publisher Copyright:
© 2022 Elsevier B.V.
PY - 2022/7
Y1 - 2022/7
N2 - Metabolic glycan labeling provides a facile yet powerful tool to install chemical tags to the cell membrane via metabolic glycoengineering processes of unnatural sugars. These cell-surface chemical tags can then mediate targeted conjugation of therapeutic agents via efficient chemistries, which has been extensively explored for cancer-targeted treatment. However, the commonly used in vivo chemistries such as azide-cyclooctyne and tetrazine-cyclooctene chemistries only allow for one-time use of cell-surface chemical tags, posing a challenge for long-term, continuous cell targeting. Here we show that cell-surface ketone groups can be recycled back to the cell membrane after covalent conjugation with hydrazide-bearing molecules, enabling repetitive targeting of hydrazide-bearing agents. Upon conjugation to ketone-labeled cancer cells via a pH-responsive hydrazone linkage, Alexa Fluor 488-hydrazide became internalized and entered endosomes/lysosomes where ketone-sugars can be released and recycled. The recycled ketone groups could then mediate targeted conjugation of Alexa Fluor 647-hydrazide. We also showed that doxorubicin-hydrazide can be targeted to ketone-labeled cancer cells for enhanced cancer cell killing. This study validates the recyclability of cell-surface chemical tags for repetitive targeting of cancer cells with the use of a reversible chemistry, which will greatly facilitate future development of potent cancer-targeted therapies based on metabolic glycan labeling.
AB - Metabolic glycan labeling provides a facile yet powerful tool to install chemical tags to the cell membrane via metabolic glycoengineering processes of unnatural sugars. These cell-surface chemical tags can then mediate targeted conjugation of therapeutic agents via efficient chemistries, which has been extensively explored for cancer-targeted treatment. However, the commonly used in vivo chemistries such as azide-cyclooctyne and tetrazine-cyclooctene chemistries only allow for one-time use of cell-surface chemical tags, posing a challenge for long-term, continuous cell targeting. Here we show that cell-surface ketone groups can be recycled back to the cell membrane after covalent conjugation with hydrazide-bearing molecules, enabling repetitive targeting of hydrazide-bearing agents. Upon conjugation to ketone-labeled cancer cells via a pH-responsive hydrazone linkage, Alexa Fluor 488-hydrazide became internalized and entered endosomes/lysosomes where ketone-sugars can be released and recycled. The recycled ketone groups could then mediate targeted conjugation of Alexa Fluor 647-hydrazide. We also showed that doxorubicin-hydrazide can be targeted to ketone-labeled cancer cells for enhanced cancer cell killing. This study validates the recyclability of cell-surface chemical tags for repetitive targeting of cancer cells with the use of a reversible chemistry, which will greatly facilitate future development of potent cancer-targeted therapies based on metabolic glycan labeling.
KW - Cell targeting
KW - Chemotherapy
KW - Click chemistry
KW - Metabolic glycan labeling
KW - cancer
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U2 - 10.1016/j.jconrel.2022.05.007
DO - 10.1016/j.jconrel.2022.05.007
M3 - Article
C2 - 35537537
AN - SCOPUS:85129744985
SN - 0168-3659
VL - 347
SP - 164
EP - 174
JO - Journal of Controlled Release
JF - Journal of Controlled Release
ER -