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Floxuridine Homomeric Oligonucleotides “Hitchhike” with Albumin In Situ for Cancer Chemotherapy
Author(s) -
Jin Cheng,
Zhang Hui,
Zou Jianmei,
Liu Yan,
Zhang Lin,
Li Fengjie,
Wang Ruowen,
Xuan Wenjing,
Ye Mao,
Tan Weihong
Publication year - 2018
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201804156
Subject(s) - chemistry , oligonucleotide , floxuridine , albumin , drug delivery , serum albumin , biochemistry , biophysics , pharmacology , cancer , fluorouracil , dna , biology , medicine , organic chemistry
Automated attachment of chemotherapeutic drugs to oligonucleotides through phosphoramidite chemistry and DNA synthesis has emerged as a powerful technology in constructing structure‐defined and payload‐tunable oligonucleotide–drug conjugates. In practice, however, in vivo delivery of these oligonucleotides remains a challenge. Inspired by the systemic transport of hydrophobic payloads by serum albumin in nature, we report the development of a lipid‐conjugated floxuridine homomeric oligonucleotide (LFU20) that “hitchhikes” with endogenous serum albumin for cancer chemotherapy. Upon intravenous injection, LFU20 immediately inserts into the hydrophobic cave of albumin to form an LFU20/albumin complex, which accumulates in the tumor by the enhanced permeability and retention (EPR) effect and internalizes into the lysosomes of cancer cells. After degradation, cytotoxic floxuridine monophosphate is released to inhibit cell proliferation.