Cargando…

Combinatorial Inhibition of Cell Surface Receptors Using Dual Aptamer-Functionalized Nanoconstructs for Cancer Treatment

Membrane receptors overexpressed in diseased states are considered novel therapeutic targets. However, the single targeting approach faces several fundamental issues, such as poor efficacy, resistance, and toxicity. Here, we report a dual-targeting strategy to enhance anti-cancer efficacy via synerg...

Descripción completa

Detalles Bibliográficos
Autores principales: Lee, Hyojin, Kim, Tae Hee, Park, Daechan, Jang, Mihue, Chung, Justin J., Kim, Soo Hyun, Kim, Sang-Heon, Lee, Kwan Hyi, Jung, Youngmee, Oh, Seung Ja
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408393/
https://www.ncbi.nlm.nih.gov/pubmed/32708267
http://dx.doi.org/10.3390/pharmaceutics12070689
_version_ 1783567822031421440
author Lee, Hyojin
Kim, Tae Hee
Park, Daechan
Jang, Mihue
Chung, Justin J.
Kim, Soo Hyun
Kim, Sang-Heon
Lee, Kwan Hyi
Jung, Youngmee
Oh, Seung Ja
author_facet Lee, Hyojin
Kim, Tae Hee
Park, Daechan
Jang, Mihue
Chung, Justin J.
Kim, Soo Hyun
Kim, Sang-Heon
Lee, Kwan Hyi
Jung, Youngmee
Oh, Seung Ja
author_sort Lee, Hyojin
collection PubMed
description Membrane receptors overexpressed in diseased states are considered novel therapeutic targets. However, the single targeting approach faces several fundamental issues, such as poor efficacy, resistance, and toxicity. Here, we report a dual-targeting strategy to enhance anti-cancer efficacy via synergistic proximity interactions between therapeutics and two receptor proteins. Importantly, we report the first finding of an interaction between c-Met and nucleolin and demonstrate the therapeutic value of targeting the interaction between them. Bispecific nanocarriers densely grafted with anti-c-Met and -nucleolin aptamer increased the local concentration of aptamers at the target sites, in addition to inducing target receptor clustering. It was also demonstrated that the simultaneous targeting of c-Met and nucleolin inhibited the cellular functions of the receptors and increased anti-cancer efficacy by altering the cell cycle. Our findings pave the way for the development of an effective combinatorial treatment based on nanoconstruct-mediated interaction between receptors.
format Online
Article
Text
id pubmed-7408393
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-74083932020-08-13 Combinatorial Inhibition of Cell Surface Receptors Using Dual Aptamer-Functionalized Nanoconstructs for Cancer Treatment Lee, Hyojin Kim, Tae Hee Park, Daechan Jang, Mihue Chung, Justin J. Kim, Soo Hyun Kim, Sang-Heon Lee, Kwan Hyi Jung, Youngmee Oh, Seung Ja Pharmaceutics Article Membrane receptors overexpressed in diseased states are considered novel therapeutic targets. However, the single targeting approach faces several fundamental issues, such as poor efficacy, resistance, and toxicity. Here, we report a dual-targeting strategy to enhance anti-cancer efficacy via synergistic proximity interactions between therapeutics and two receptor proteins. Importantly, we report the first finding of an interaction between c-Met and nucleolin and demonstrate the therapeutic value of targeting the interaction between them. Bispecific nanocarriers densely grafted with anti-c-Met and -nucleolin aptamer increased the local concentration of aptamers at the target sites, in addition to inducing target receptor clustering. It was also demonstrated that the simultaneous targeting of c-Met and nucleolin inhibited the cellular functions of the receptors and increased anti-cancer efficacy by altering the cell cycle. Our findings pave the way for the development of an effective combinatorial treatment based on nanoconstruct-mediated interaction between receptors. MDPI 2020-07-21 /pmc/articles/PMC7408393/ /pubmed/32708267 http://dx.doi.org/10.3390/pharmaceutics12070689 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Lee, Hyojin
Kim, Tae Hee
Park, Daechan
Jang, Mihue
Chung, Justin J.
Kim, Soo Hyun
Kim, Sang-Heon
Lee, Kwan Hyi
Jung, Youngmee
Oh, Seung Ja
Combinatorial Inhibition of Cell Surface Receptors Using Dual Aptamer-Functionalized Nanoconstructs for Cancer Treatment
title Combinatorial Inhibition of Cell Surface Receptors Using Dual Aptamer-Functionalized Nanoconstructs for Cancer Treatment
title_full Combinatorial Inhibition of Cell Surface Receptors Using Dual Aptamer-Functionalized Nanoconstructs for Cancer Treatment
title_fullStr Combinatorial Inhibition of Cell Surface Receptors Using Dual Aptamer-Functionalized Nanoconstructs for Cancer Treatment
title_full_unstemmed Combinatorial Inhibition of Cell Surface Receptors Using Dual Aptamer-Functionalized Nanoconstructs for Cancer Treatment
title_short Combinatorial Inhibition of Cell Surface Receptors Using Dual Aptamer-Functionalized Nanoconstructs for Cancer Treatment
title_sort combinatorial inhibition of cell surface receptors using dual aptamer-functionalized nanoconstructs for cancer treatment
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408393/
https://www.ncbi.nlm.nih.gov/pubmed/32708267
http://dx.doi.org/10.3390/pharmaceutics12070689
work_keys_str_mv AT leehyojin combinatorialinhibitionofcellsurfacereceptorsusingdualaptamerfunctionalizednanoconstructsforcancertreatment
AT kimtaehee combinatorialinhibitionofcellsurfacereceptorsusingdualaptamerfunctionalizednanoconstructsforcancertreatment
AT parkdaechan combinatorialinhibitionofcellsurfacereceptorsusingdualaptamerfunctionalizednanoconstructsforcancertreatment
AT jangmihue combinatorialinhibitionofcellsurfacereceptorsusingdualaptamerfunctionalizednanoconstructsforcancertreatment
AT chungjustinj combinatorialinhibitionofcellsurfacereceptorsusingdualaptamerfunctionalizednanoconstructsforcancertreatment
AT kimsoohyun combinatorialinhibitionofcellsurfacereceptorsusingdualaptamerfunctionalizednanoconstructsforcancertreatment
AT kimsangheon combinatorialinhibitionofcellsurfacereceptorsusingdualaptamerfunctionalizednanoconstructsforcancertreatment
AT leekwanhyi combinatorialinhibitionofcellsurfacereceptorsusingdualaptamerfunctionalizednanoconstructsforcancertreatment
AT jungyoungmee combinatorialinhibitionofcellsurfacereceptorsusingdualaptamerfunctionalizednanoconstructsforcancertreatment
AT ohseungja combinatorialinhibitionofcellsurfacereceptorsusingdualaptamerfunctionalizednanoconstructsforcancertreatment