Locally unlocks prodrugs by radiopharmaceutical in tumor for cancer therapy

Changlun Wang ¹Mengxin Xu ²Zihang Zhang ¹Senhai Zeng ¹Siyong Shen ¹Zexuan Ding ³Junyi Chen ¹Xi-Yang Cui ³Zhibo Liu⁴

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作者信息

1. Beijing National Laboratory for Molecular Sciences,Radiochemistry and Radiation Chemistry Key Laboratory of Fundamental Science,Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education,College of Chemistry and Molecular Engineering,Peking University,Beijing 100871,China
2. Beijing National Laboratory for Molecular Sciences,Radiochemistry and Radiation Chemistry Key Laboratory of Fundamental Science,Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education,College of Chemistry and Molecular Engineering,Peking University,Beijing 100871,China;Changping Laboratory,Beijing 102206,China
3. Changping Laboratory,Beijing 102206,China
4. Beijing National Laboratory for Molecular Sciences,Radiochemistry and Radiation Chemistry Key Laboratory of Fundamental Science,Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education,College of Chemistry and Molecular Engineering,Peking University,Beijing 100871,China;Peking University-Tsinghua University Center for Life Sciences,Peking University,Beijing 100871,China;Changping Laboratory,Beijing 102206,China;Key Laboratory of Carcinogenesis and Translational Research of M
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Abstract

Chemotherapy is the first-line treatment for cancer,but its systemic toxicity can be severe.Tumor-selective prodrug activation offers promising opportunities to reduce systemic toxicity.Here,we present a strategy for activating prodrugs using radiopharmaceuticals.This strategy enables the targeted release of chemotherapeutic agents due to the high tumor-targeting capability of radiopharmaceuticals.[18F]FDG(2-[18F]-fluoro-2-deoxy-D-glucose),one of the most widely used radiopharmaceuticals in clinics,can trig-ger Pt(Ⅳ)complex for controlled release of axial ligands in tumors,it might be mediated by hydrated electrons generated by water radiolysis resulting from the decay of radionuclide 18F.Its application offers the controlled release of fluorogenic probes and prodrugs in living cells and tumor-bearing mice.Of note,an OxaliPt(Ⅳ)linker is designed to construct an[18F]FDG-activated antibody-drug conjugate(Pt-ADC).Sequential injection of Pt-ADC and[18F]FDG efficiently releases the toxin in the tumor and remarkably suppresses the tumor growth.Radiotherapy is booming as a perturbing tool for prodrug activation,and we find that[18F]FDG is capable of deprotecting various radiotherapy-removable protecting groups(RPGs).Our results suggest that tumor-selective radiopharmaceutical may function as a trigger,for devel-oping innovative prodrug activation strategies with enhanced tumor selectivity.

Key words

Prodrug activation/Radiopharmaceutical/Radiochemistry/[18F]FDG/Platinum(Ⅳ)prodrug

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基金项目

Beijing Municipal Natural Science Foundation(Z200018)

National Natural Science Foundation of China(22225603)

Ministry of Science and Technology of the People's Republic of China(2021YFA1601400)

Program of the Local Science and Technology Development(Gansu Province)Guided by Central Government(YDZX20216200001201)

Changping Laboratory()

Central Guidance for Local Science and Technology Development Projects(202138-03)

Analytical Instrumentation Center of Peking University()

出版年

2024

科学通报(英文版)

中国科学院

科学通报(英文版)

CSTPCD

ISSN：1001-6538

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