Hypoxia-Activated Anticancer Prodrug for Bioimaging, Tracking Drug Release, and Anticancer Application

Liu, Wei; Liu, Haitong; Peng, Xiaoran; Zhou, Guoqiang; Liu, Dandan; Li, Shenghui; Zhang, Jinchao; Wang, Shuxiang

doi:10.1021/acs.bioconjchem.8b00511

Cited by 27 publications

(16 citation statements)

References 46 publications

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“…Considering the high molar absorption coefficient and quantum yield of coumarins. 37 The optical characteristics of AUR, CD@AUR and CDDP HA-CD@AUR were detected by fluorescence spectroscopy. As depicted in Figure 5 , the emission peaks of all three appear at 453 nm at the excitation wavelength of 370 nm and the fluorescence intensity of CD@AUR and nanogel were enhanced significantly.…”

Section: Resultsmentioning

confidence: 99%

<p>pH-Responsive Fluorescence Enhanced Nanogel for Targeted Delivery of AUR and CDDP Against Breast Cancer</p>

Cao¹,

Li²,

Li³

et al. 2020

IJN

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Introduction Auraptene (AUR), a natural bioactive prenyloxy coumarin, is a highly pleiotropic molecule that can bind to the MT1 receptor and can effectively reduce the proliferation and migration of breast cancer cells. Cisplatin (CDDP), as the first synthetic platinum-based anticancer drug, is widely used in the clinic due to its definite mechanism and therapeutic effect on diverse tumors. However, both of AUR and CDDP exhibit some disadvantages when used alone, including poor solubility, low bioavailability, lack of selectivity and systemic toxicity when they are used singly. Methods Therefore, the biodegradable materials hyaluronic acid (HA) and β-cyclodextrin derivative (mono-(6-amino-mono-6-deoxy)-β-CD, CD) were employed as carriers to load AUR and CDDP to form nanogel ( CDDP HA-CD@AUR) capable of dual-targeted delivery and synergistic therapy for breast cancer and cell imaging. Results With the help of the CDDP-crosslinked CD-loaded structure, the newly synthesized nanogel exhibited excellent physiological stability and fluorescence effects. The release of AUR and CDDP was affected by the pH value, which was beneficial to the selective release in the tumor microenvironment. Cell experiments in vitro demonstrated that the nanogel could be selectively internalized by MCF-7 cells and exhibited low cytotoxicity to HK-2 cells. Antitumor experiments in vivo showed that the nanogel have better antitumor effects and lower systemic toxicity. Conclusion Based on these, the nanogel loaded with AUR and CDDP have the potential for targeted delivery against breast cancer.

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Section: Resultsmentioning

confidence: 99%

<p>pH-Responsive Fluorescence Enhanced Nanogel for Targeted Delivery of AUR and CDDP Against Breast Cancer</p>

Cao¹,

Li²,

Li³

et al. 2020

IJN

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“…These results provided evidence for the release of FDU and IMC-TZBCM from the prodrug IMC-FDU-TZBC-NO 2 . Based on the results above and combined with reports, ,− the process of releasing FDU with IMC-TZBCM from IMC-FDU-TZBC-NO 2 is depicted as follows: first, under the action of Na 2 S 2 O 4 the −NO 2 group was converted to −NH 2 , and IMC-FDU-TZBC-NO 2 was reduced to IMC-FDU-TZBC-NH 2 . Immediately following a series of electron transfer process and the 1,6-rearrangement-elimination reaction, small molecule 4-methylenecyclohexa-2,5-dien-1-iminium was eliminated, leading to production of IMC-FDU-TZBC.…”

Section: Resultsmentioning

confidence: 99%

Hypoxia-Activated and Indomethacin-Mediated Theranostic Prodrug Releasing Drug On-Demand for Tumor Imaging and Therapy

et al. 2019

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A smart theranostic prodrug IMC-FDU-TZBC-NO 2 , releasing active drug on-demand based on hypoxiaactivated and indomethacin-mediated, for solid tumor imaging and efficient therapy was designed. This prodrug was constructed by conjugating chemotherapy drug 5-fluoro-2-deoxyuridine (FDU), targeting moiety indomethacin (IMC), and the hypoxic trigger 4-nitrobenzyl group to a fluorescent dye precursor, which was mediated by IMC and activated by NTR under hypoxic conditions. The fluorescent dye IMC-TZBCM was generated and FDU was released at the same time in tumor cells. The rates and amounts of FDU release and IMC-TZBCM generation were regulated by hypoxia status, and increased with increasing degree of hypoxia. Nevertheless, it is "locked" in normal cells. It combined the advantages of tumor targeting, diagnosis, and chemotherapy functions, showed excellent targeting ability to cancer cells, excellent stability in physiological conditions, high cellular uptake efficiency, and on-demand drug release behavior. The in vitro and in vivo assays demonstrated that IMC-FDU-TZBC-NO 2 exhibits enhanced anticancer potency and low side effects. The novel targeted theranostic prodrug activated by hypoxia shows a great potential in cancer therapy.

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“…Liu et al [26] designed a novel prodrug (FDU-DB-NO2: 16) that on bioreductive fragmentation released not only the antimetabolite floxuridine (17), but simultaneously generated the fluorescent dye 4 -(diethylamino)-1,1 -biphenyl-2-carboxylate (18); the latter for real-time tracking of drug release. The prodrug 16 was evaluated under normoxic and hypoxic cultures of MCF-7 breast cancer and MCG-803 human gastric cancer cells, where it showed good activity (Figure 4).…”

Section: -Nitrobenzyl Triggersmentioning

confidence: 99%

Nitroaromatic Hypoxia-Activated Prodrugs for Cancer Therapy

Denny

2022

Pharmaceuticals

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The presence of “hypoxic” tissue (with O2 levels of <0.1 mmHg) in solid tumours, resulting in quiescent tumour cells distant from blood vessels, but capable of being reactivated by reoxygenation following conventional therapy (radiation or drugs), have long been known as a limitation to successful cancer chemotherapy. This has resulted in a sustained effort to develop nitroaromatic “hypoxia-activated prodrugs” designed to undergo enzyme-based nitro group reduction selectively in these hypoxic regions, to generate active drugs. Such nitro-based prodrugs can be classified into two major groups; those activated either by electron redistribution or by fragmentation following nitro group reduction, relying on the extraordinary difference in electron demand between an aromatic nitro group and its reduction products. The vast majority of hypoxia-activated fall into the latter category and are discussed here classed by the nature of their nitroaromatic trigger units.

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Hypoxia-Activated Anticancer Prodrug for Bioimaging, Tracking Drug Release, and Anticancer Application

Cited by 27 publications

References 46 publications

<p>pH-Responsive Fluorescence Enhanced Nanogel for Targeted Delivery of AUR and CDDP Against Breast Cancer</p>

<p>pH-Responsive Fluorescence Enhanced Nanogel for Targeted Delivery of AUR and CDDP Against Breast Cancer</p>

Hypoxia-Activated and Indomethacin-Mediated Theranostic Prodrug Releasing Drug On-Demand for Tumor Imaging and Therapy

Nitroaromatic Hypoxia-Activated Prodrugs for Cancer Therapy

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