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^*

^*Corresponding author for this work

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

27 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

UN SDGs

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

SDG 3 Good Health and Well-being

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

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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",

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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 - https://www.scopus.com/pages/publications/85138095706

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

UN SDGs

Keywords

ASJC Scopus subject areas

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