Enhanced Tumor Selectivity of 5-Fluorouracil Using a Reactive Oxygen Species-Activated Prodrug Approach

Ai, Yong; Obianom, Obinna N.; Kuser, Meredith; Li, Yue; Shu, Yan; Xue, Fengtian

doi:10.1021/acsmedchemlett.8b00539

Cited by 29 publications

(45 citation statements)

References 35 publications

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“…This is distinctively different from many published reports that the entire benzylboronic acid/ester group would be lost after H 2 O 2 treatment. 18,20,[22][23]25 Previously Rokita group and Peng group have shown that the substituents on o-quinone methide (o-QM) precursors strongly affect o-QM's formation and reactivity [32][33][34] . In the case of CQB, we suspect the strong electron deficiency of quinazolinone scaffold as well as the conjugation of CQ with methylene phenol at amide bond prevents its removal.…”

Section: Cqb Can Be Cascade-activated By Ros and Tyr In Aqueous Buffermentioning

confidence: 99%

A Reactive Oxygen Species-Tyrosinase Cascade-Activated Prodrug for Selectively Suppressing Melanoma

Yang

Zhang

et al. 2022

CCS Chem

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Off-target effect" is one of the obstacles for targeted prodrugs in chemotherapy. To circumvent this issue, herein we proposed a dual biomarker cascade-activated prodrug strategy based on high levels of reactive oxygen species (ROS) and tyrosinase (TYR) in melanoma cells. A representative prodrug, Coumarin-Quinazolinone-phenylBoronic acid pinacol ester (CQB) was prepared. The prodrug contained coumarinquinazolinone (CQ) as mitochondria targeting and monitoring moiety, and phenylboronic acid pinacol ester as a cascade-activated pro-warhead. After activated by the endogenous ROS and subsequent TYR in melanoma cells, CQB can be converted to the final active reagent Coumarin-Quinazolinone-o-Quinone (CQQ) which

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Section: Cqb Can Be Cascade-activated By Ros and Tyr In Aqueous Buffermentioning

confidence: 99%

A Reactive Oxygen Species-Tyrosinase Cascade-Activated Prodrug for Selectively Suppressing Melanoma

Yang

Zhang

et al. 2022

CCS Chem

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“…Further reaction of the -SOH group with nearby a cysteine leads to disulfide bond formation and/or result in changes in the structure and function of various proteins. 99 Recently, Ai et al 103 concentrations used in all these in vitro experiments were on the high side. Prodrug 54a was tested in wild-type C57BL/6 male mice for safety.…”

Section: Thiol-sensitive Linkersmentioning

confidence: 99%

“…Recently, Ai et al 103 designed boronic acid‐ and boronate‐based prodrugs of 5‐fluorouracil (5‐FU). 5‐FU is generally used to treat solid tumors of the breast, stomach, colon, and pancreas.…”

Section: Reactive Oxygen Species (Ros) Sensitive Linkersmentioning

confidence: 99%

Making smart drugs smarter: The importance of linker chemistry in targeted drug delivery

Yang

Pan

Choudhury

et al. 2020

Medicinal Research Reviews

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Smart drugs, such as antibody-drug conjugates, for targeted therapy rely on the ability to deliver a warhead to the desired location and to achieve activation at the same site. Thus, designing a smart drug often requires proper linker chemistry for tethering the warhead with a vehicle in such a way that either allows the active drug to retain its potency while being tethered or ensures release and thus activation at the desired location. Recent years have seen much progress in the design of new linker activation strategies. Herein, we review the recent development of chemical strategies used to link the warhead with a delivery vehicle for preferential cleavage at the desired sites. K E Y W O R D S antibody-drug conjugates, click and release, drug delivery, linker chemistry, targeted delivery, triggered release 1 | INTRODUCTION In the world of drug discovery and development, the concept of "smart drugs" broadly refers to those that can selectively affect disease-relevant target(s). However, to a certain degree, essentially all drugs are already selective toward the desired target(s) whether they are enzyme inhibitors, receptor ligands, ion channel blockers, inhibitors of protein-protein interaction, or even genotoxins used for cancer chemotherapy, among others. They would not have made through the various milestones of drug discovery and developmental processes if they were not sufficiently selective for the intended target(s). However, once administered into the human body, the highly complex living system often leads to many unexpected off-target effects. Thus, various additional approaches have been studied and

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“…For the past 70 decades, fluoropyrimidine 5-fluorouracil (5FU) has been widely utilized as a frontline medication for the treatment of a wide variety of tumors, including colon, cervical, lung, and breast cancers. When given intravenously, it is aqueous soluble and stable (De Luca et al, 2016 ; Ai et al, 2019 ; Dai et al, 2020 ; Moorkoth et al, 2021 ). However, for early colorectal cancer, 5FU has a response rate ∼15%, and its biocompatibility decreases life times.…”

Section: Introductionmentioning

confidence: 99%

Engineering of hybrid anticancer drug-loaded polymeric nanoparticles delivery system for the treatment and care of lung cancer therapy

Zhao

Liu

et al. 2021

Drug Delivery

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Chemotherapy with combination drugs has become one of the most commonly used cancer prevention treatments, with positive clinical results. The goal of this study was to develop compostable polymeric nanomaterials (NMs) for the delivery of puerarin (PRN) and 5-fluorouracil (5FU), as well as to investigate the anticancer activity of the drug delivery system (PRN-5FU NMs) against in vitro and in vivo lung cancer cells. Since double antitumor drugs PRN and 5FU are insufficiently compressed in polymer-based bio-degradable nanoparticles, encapsulation of PRN and 5FU antitumor drugs were coencapsulated with polyethylene glycol and polylactidecoglycolide nanoparticles (NMs) is efficient. The arrangement of PRN NMs, 5FU NMs, and PRN-5FU NMs, as well as the nanoparticles shape and scale, were studied using transmission electron microscopy (TEM). 5FU-PRN NMs triggered apoptosis in lung carcinoma cell lines such as HEL-299 and A549 in vitro. Acridine orange/ethidium bromide (AO/EB) and nuclear damaging staining techniques were used to observe morphologies and cell death. The mechanistic analysis of apoptosis was also confirmed by flow cytometry analysis using dual staining. When compared to free anticancer products, the hemolysis analysis findings of the 5FU-PRN NMs showed excellent biocompatibility. Taken together the advantages, this combination drug conveyance strategy exposed that 5FU-PRN NMs could have a significant promising to improve the effectiveness of lung cancer cells.

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Enhanced Tumor Selectivity of 5-Fluorouracil Using a Reactive Oxygen Species-Activated Prodrug Approach

Cited by 29 publications

References 35 publications

A Reactive Oxygen Species-Tyrosinase Cascade-Activated Prodrug for Selectively Suppressing Melanoma

A Reactive Oxygen Species-Tyrosinase Cascade-Activated Prodrug for Selectively Suppressing Melanoma

Making smart drugs smarter: The importance of linker chemistry in targeted drug delivery

Engineering of hybrid anticancer drug-loaded polymeric nanoparticles delivery system for the treatment and care of lung cancer therapy

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