A highly GSH-sensitive SN-38 prodrug with an “OFF-to-ON” fluorescence switch as a bifunctional anticancer agent

Whang, Chang-Hee; Yoo, Eunsoo; Hur, Seong Kwon; Kim, Kyeong Soo; Kim, Dongin; Jo, Seong Mu

doi:10.1039/c8cc05010d

Cited by 34 publications

(28 citation statements)

References 31 publications

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“…The possibility of deactivation of prodrugs by thiol-containing species was also investigated. The prodrugs 1 – 3 were treated with glutathione (GSH), but no reaction was observed (Supporting Information).…”

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confidence: 99%

A Bioreductive Prodrug of Cucurbitacin B Significantly Inhibits Tumor Growth in the 4T1 Xenograft Mice Model

Suebsakwong

Wang

Khetkam

et al. 2019

ACS Med. Chem. Lett.

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Cucurbitacin B (CuB), a highly cytotoxic constituent of the Cucurbitaceae plant, was identified to exhibit potent inhibitory activity against human cancer cells as well as normal cells. This disadvantage hampers the possibility of developing this compound into an anticancer drug candidate. In this work, several bioreductive prodrugs of CuB were designed to reduce toxicity to normal cells while maintaining the cytotoxic effect to cancer cells. Embedded with a bioreductive delivery and cleavable system in cancer tissues, cucurbitacin B-based prodrugs 1, 2, and 3 were synthesized and evaluated by in vitro and in vivo experiments. Compared with the parent CuB, prodrug 1 was found to significantly reduce the toxicity down to 310-fold lower against noncancerous cells. LC-MS analyses show that prodrug 1 efficiently releases the parent compound in the reductase-overexpressed MCF-7 cells. In addition, prodrug 1 shows satisfactory and comparable effectiveness in controlling tumor growth as that by tamoxifen in the 4T1 xenograft mice model.

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confidence: 99%

A Bioreductive Prodrug of Cucurbitacin B Significantly Inhibits Tumor Growth in the 4T1 Xenograft Mice Model

Suebsakwong

Wang

Khetkam

et al. 2019

ACS Med. Chem. Lett.

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“…The tumor microenvironment (TME) is known to encompass unique physicochemical properties that are significantly different from those of the normal tissues. One of the main highlights is generally accepted to be the elevated oxidative stress resulting from the overproduction of reactive oxygen species (ROS) by hypoxic conditions in various TME-associated cells; 36 and another is the acidic TME, which is a consequence of accelerated glycolysis and/or oxidative phosphorylation that provide energy and chemical intermediates for cancer cell proliferation. 36 The nanocarriers prepared in this study contained GSH and pH sensitive prodrug.…”

Section: Discussionmentioning

confidence: 99%

“…One of the main highlights is generally accepted to be the elevated oxidative stress resulting from the overproduction of reactive oxygen species (ROS) by hypoxic conditions in various TME-associated cells; 36 and another is the acidic TME, which is a consequence of accelerated glycolysis and/or oxidative phosphorylation that provide energy and chemical intermediates for cancer cell proliferation. 36 The nanocarriers prepared in this study contained GSH and pH sensitive prodrug. The GSH sensitive prodrug-based nanocarriers have been designed by researchers and gained excellent anticancer effect.…”

Section: Discussionmentioning

confidence: 99%

<p>Synergistic Combination Chemotherapy of Lung Cancer: Cisplatin and Doxorubicin Conjugated Prodrug Loaded, Glutathione and pH Sensitive Nanocarriers</p>

Jin

Wang

Liu

et al. 2020

DDDT

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Prodrug technology-based combination drug therapy has been exploited as a promising treatment strategy to achieve synergistic lung cancer therapy, reduce drug dose, and decrease side effects. In the present study, we synthesized a pH and glutathione (GSH) sensitive prodrug, cisplatin (CIS) and doxorubicin (DOX) conjugates (CIS-DOXp). CIS-DOXp was loaded by nanocarriers and delivered into the tumor site. Methods: pH and GSH sensitive CIS-DOX prodrug (CIS-DOXp) was synthesized by conjugating GSH responsive CIS prodrug with pH sensitive DOX prodrug. CIS-DOXp-loaded nanocarriers (CIS-DOXp NC) were prepared using emulsification and solvent evaporation method. The morphology, particle size, polydispersity index (PDI) and zeta potential of nanocarriers were measured. In vitro cytotoxicity of nanocarriers and the corresponding free drugs was examined using the MTT assay. In vivo anti-tumor efficiency and biodistribution behaviors were evaluated on lung cancer mice models. Results: The size, PDI, zeta potential, CIS loading efficiency, and DOX loading efficiency of CIS-DOXp NC were 128.6 ± 3.2 nm, 0.196 ± 0.021, 15.7 ± 1.7 mV, 92.1 ± 2.1%, and 90.4 ± 1.8%, respectively. The best cell killing ability (the lowest combination index of 0.57) was found at the combination ratio of 1:3 (CIS:DOX, w/w) in the drugs co-loaded formulations, indicating the strongest synergism effect. CIS-DOXp NC showed the best tumor inhibition efficiency (79.9%) in mice with negligible body weight lost. Conclusion: CIS-DOXp NC could be applied as a promising system for the synergistic chemotherapy of lung cancer.

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“…Irinotecan (I), a water-soluble prodrug of SN38 (7-ethyl-10-camptothecin), its property of lower transforming ratio to the active metabolite (only 2–8 percent) makes researchers devoted themselves to novel strategies for improving its therapeutic effect (Slatter et al., 1997 ; Mathijssen et al., 2001 ). Those strategies include prodrug technology and nanocarriers (Wang et al., 2013 ; Whang et al., 2018 ; Xing et al., 2019 ). Herein, based on present studies, further CRC tumor-targeted lipid nanoparticles were engineered by combining lipid prodrug strategy, reactive oxygen species (ROS) sensitive technology and lipid carriers.…”

Section: Introductionmentioning

confidence: 99%

Combined and targeted drugs delivery system for colorectal cancer treatment: Conatumumab decorated, reactive oxygen species sensitive irinotecan prodrug and quercetin co-loaded nanostructured lipid carriers

et al. 2022

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Purpose Colorectal cancer (CRC) is the third most frequently diagnosed cancer and this study aimed to develop a conatumumab decorated, irinotecan prodrug and quercetin co-loaded delivery system for combined and targeted colorectal cancer treatment. Methods A conatumumab (C) decorated, irinotecan prodrug (I-p) and quercetin (Q) co-encapsulated NLC (C I-p/Q NLC) was developed. In vitro and in vivo antitumor efficiency of NLC was evaluated on CRC cells and mice xenograft. Results The results showed that the HT-29 cells uptake of C I-p/Q NLC was over 70%. Reactive oxygen species (ROS) sensitive irinotecan prodrug formulation showed improved drug release ability in hypoxic conditions. C I-p/Q NLC showed significantly higher cytotoxicity than non-decorated NLC, single drug-loaded NLC and free drugs. In vivo studies in a CRC-bearing model corroborated the capability of nanoparticles for the inhibition of cancer, leading to a reduction of tumor growth without systemic toxicity. Conclusion The conatumumab decorated, ROS sensitive prodrug contained combination nano-system is a promising platform for CRC therapy.

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A highly GSH-sensitive SN-38 prodrug with an “OFF-to-ON” fluorescence switch as a bifunctional anticancer agent

Cited by 34 publications

References 31 publications

A Bioreductive Prodrug of Cucurbitacin B Significantly Inhibits Tumor Growth in the 4T1 Xenograft Mice Model

A Bioreductive Prodrug of Cucurbitacin B Significantly Inhibits Tumor Growth in the 4T1 Xenograft Mice Model

<p>Synergistic Combination Chemotherapy of Lung Cancer: Cisplatin and Doxorubicin Conjugated Prodrug Loaded, Glutathione and pH Sensitive Nanocarriers</p>

Combined and targeted drugs delivery system for colorectal cancer treatment: Conatumumab decorated, reactive oxygen species sensitive irinotecan prodrug and quercetin co-loaded nanostructured lipid carriers

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