A synchronized dual drug delivery molecule targeting cancer stem cells in tumor heterogeneity and metastasis

Ji Hyeon Kim; Jung Min Park; Eunsun Jung; Jieun Lee; Jiyou Han; Yoon Jae Kim; Ji Young Kim; Jae Hong Seo; Jong Seung Kim

doi:10.1016/j.biomaterials.2022.121781

A synchronized dual drug delivery molecule targeting cancer stem cells in tumor heterogeneity and metastasis

Ji Hyeon Kim, Jung Min Park, Eunsun Jung, Jieun Lee, Jiyou Han, Yoon Jae Kim, Ji Young Kim, Jae Hong Seo, Jong Seung Kim

Research output: Contribution to journal › Article › peer-review

21 Citations (Scopus)

Abstract

Cancer stem-like cells (CSCs) represent a key barrier to successful therapy for triple-negative breast cancer (TNBC). CSCs promote the emergence of chemoresistance, triggering relapse and resulting in a poor prognosis. We herein present CDF-TM, a new small molecule-based binary prodrug conjugated with SN-38 and 3,4-difluorobenzylidene curcumin (CDF) that is specifically activated in hypoxic conditions. CDF-TM treatment significantly induced apoptosis in TNBC-derived 3D spheroids, accompanied with caspase-3 activation as well as the attenuation of tumor stemness with evidence of reduction in aldehyde dehydrogenase 1 (ALDH1) activity and the CD44^high/CD24^low phenotype. An in vivo orthotopic allograft model was used to investigate its effects on tumor growth and metastasis. The dissemination of CSCs from primary allografts was impaired by CDF-TM, along with inhibition of tumor growth via eradication of CSCs and downregulation of multidrug resistance 1 (MDR1). This new small molecule-based binary prodrug offers a novel therapeutic option for metastatic TNBC.

Original language	English
Article number	121781
Journal	Biomaterials
Volume	289
DOIs	https://doi.org/10.1016/j.biomaterials.2022.121781
Publication status	Published - 2022 Oct

Bibliographical note

Funding Information:
This research was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare , Republic of Korea (grant number: HR20C0021 ), the National Research Foundation of Korea (NRF) (grant number: 2018R1A3B1052702 , 2019M3E5D1A01068998 , 2021R1A2C2009723 , 2019H1A2A1074096 ), and was supported by the Brain Korea (BK) 21 Plus Program .

Funding Information:
This research was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HR20C0021), the National Research Foundation of Korea (NRF) (grant number: 2018R1A3B1052702, 2019M3E5D1A01068998, 2021R1A2C2009723, 2019H1A2A1074096), and was supported by the Brain Korea (BK) 21 Plus Program.

Publisher Copyright:
© 2022 Elsevier Ltd

Keywords

Binary prodrug
Cancer stem cells
MDR1
Metastasis
Triple-negative breast cancer

ASJC Scopus subject areas

Mechanics of Materials
Ceramics and Composites
Bioengineering
Biophysics
Biomaterials

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.biomaterials.2022.121781

Cite this

@article{88a0cb6c9f724ae7ac4f362a08f1f87a,

title = "A synchronized dual drug delivery molecule targeting cancer stem cells in tumor heterogeneity and metastasis",

abstract = "Cancer stem-like cells (CSCs) represent a key barrier to successful therapy for triple-negative breast cancer (TNBC). CSCs promote the emergence of chemoresistance, triggering relapse and resulting in a poor prognosis. We herein present CDF-TM, a new small molecule-based binary prodrug conjugated with SN-38 and 3,4-difluorobenzylidene curcumin (CDF) that is specifically activated in hypoxic conditions. CDF-TM treatment significantly induced apoptosis in TNBC-derived 3D spheroids, accompanied with caspase-3 activation as well as the attenuation of tumor stemness with evidence of reduction in aldehyde dehydrogenase 1 (ALDH1) activity and the CD44high/CD24low phenotype. An in vivo orthotopic allograft model was used to investigate its effects on tumor growth and metastasis. The dissemination of CSCs from primary allografts was impaired by CDF-TM, along with inhibition of tumor growth via eradication of CSCs and downregulation of multidrug resistance 1 (MDR1). This new small molecule-based binary prodrug offers a novel therapeutic option for metastatic TNBC.",

keywords = "Binary prodrug, Cancer stem cells, MDR1, Metastasis, Triple-negative breast cancer",

author = "Kim, {Ji Hyeon} and Park, {Jung Min} and Eunsun Jung and Jieun Lee and Jiyou Han and Kim, {Yoon Jae} and Kim, {Ji Young} and Seo, {Jae Hong} and Kim, {Jong Seung}",

note = "Funding Information: This research was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare , Republic of Korea (grant number: HR20C0021 ), the National Research Foundation of Korea (NRF) (grant number: 2018R1A3B1052702 , 2019M3E5D1A01068998 , 2021R1A2C2009723 , 2019H1A2A1074096 ), and was supported by the Brain Korea (BK) 21 Plus Program . Funding Information: This research was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HR20C0021), the National Research Foundation of Korea (NRF) (grant number: 2018R1A3B1052702, 2019M3E5D1A01068998, 2021R1A2C2009723, 2019H1A2A1074096), and was supported by the Brain Korea (BK) 21 Plus Program. Publisher Copyright: {\textcopyright} 2022 Elsevier Ltd",

year = "2022",

month = oct,

doi = "10.1016/j.biomaterials.2022.121781",

language = "English",

volume = "289",

journal = "Biomaterials",

issn = "0142-9612",

publisher = "Elsevier Ltd",

}

TY - JOUR

T1 - A synchronized dual drug delivery molecule targeting cancer stem cells in tumor heterogeneity and metastasis

AU - Kim, Ji Hyeon

AU - Park, Jung Min

AU - Jung, Eunsun

AU - Lee, Jieun

AU - Han, Jiyou

AU - Kim, Yoon Jae

AU - Kim, Ji Young

AU - Seo, Jae Hong

AU - Kim, Jong Seung

N1 - Funding Information: This research was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare , Republic of Korea (grant number: HR20C0021 ), the National Research Foundation of Korea (NRF) (grant number: 2018R1A3B1052702 , 2019M3E5D1A01068998 , 2021R1A2C2009723 , 2019H1A2A1074096 ), and was supported by the Brain Korea (BK) 21 Plus Program . Funding Information: This research was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HR20C0021), the National Research Foundation of Korea (NRF) (grant number: 2018R1A3B1052702, 2019M3E5D1A01068998, 2021R1A2C2009723, 2019H1A2A1074096), and was supported by the Brain Korea (BK) 21 Plus Program. Publisher Copyright: © 2022 Elsevier Ltd

PY - 2022/10

Y1 - 2022/10

N2 - Cancer stem-like cells (CSCs) represent a key barrier to successful therapy for triple-negative breast cancer (TNBC). CSCs promote the emergence of chemoresistance, triggering relapse and resulting in a poor prognosis. We herein present CDF-TM, a new small molecule-based binary prodrug conjugated with SN-38 and 3,4-difluorobenzylidene curcumin (CDF) that is specifically activated in hypoxic conditions. CDF-TM treatment significantly induced apoptosis in TNBC-derived 3D spheroids, accompanied with caspase-3 activation as well as the attenuation of tumor stemness with evidence of reduction in aldehyde dehydrogenase 1 (ALDH1) activity and the CD44high/CD24low phenotype. An in vivo orthotopic allograft model was used to investigate its effects on tumor growth and metastasis. The dissemination of CSCs from primary allografts was impaired by CDF-TM, along with inhibition of tumor growth via eradication of CSCs and downregulation of multidrug resistance 1 (MDR1). This new small molecule-based binary prodrug offers a novel therapeutic option for metastatic TNBC.

AB - Cancer stem-like cells (CSCs) represent a key barrier to successful therapy for triple-negative breast cancer (TNBC). CSCs promote the emergence of chemoresistance, triggering relapse and resulting in a poor prognosis. We herein present CDF-TM, a new small molecule-based binary prodrug conjugated with SN-38 and 3,4-difluorobenzylidene curcumin (CDF) that is specifically activated in hypoxic conditions. CDF-TM treatment significantly induced apoptosis in TNBC-derived 3D spheroids, accompanied with caspase-3 activation as well as the attenuation of tumor stemness with evidence of reduction in aldehyde dehydrogenase 1 (ALDH1) activity and the CD44high/CD24low phenotype. An in vivo orthotopic allograft model was used to investigate its effects on tumor growth and metastasis. The dissemination of CSCs from primary allografts was impaired by CDF-TM, along with inhibition of tumor growth via eradication of CSCs and downregulation of multidrug resistance 1 (MDR1). This new small molecule-based binary prodrug offers a novel therapeutic option for metastatic TNBC.

KW - Binary prodrug

KW - Cancer stem cells

KW - MDR1

KW - Metastasis

KW - Triple-negative breast cancer

UR - http://www.scopus.com/inward/record.url?scp=85138095706&partnerID=8YFLogxK

U2 - 10.1016/j.biomaterials.2022.121781

DO - 10.1016/j.biomaterials.2022.121781

M3 - Article

C2 - 36113331

AN - SCOPUS:85138095706

SN - 0142-9612

VL - 289

JO - Biomaterials

JF - Biomaterials

M1 - 121781

ER -

A synchronized dual drug delivery molecule targeting cancer stem cells in tumor heterogeneity and metastasis

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this