Cargando…

A Designer Nanoparticle Platform for Controlled Intracellular Delivery of Bioactive Macromolecules: Inhibition of Ubiquitin-Specific Protease 7 in Breast Cancer Cells

[Image: see text] Biological therapeutics represent an increasing and critical component of newly approved drugs; however, the inability to deliver biologics intracellularly in a controlled manner remains a major limitation. We have developed a semi-synthetic, tunable phage-like particle (PLP) platf...

Descripción completa

Detalles Bibliográficos
Autores principales: McClary, Wynton D., Catala, Alexis, Zhang, Wei, Gamboni, Fabia, Dzieciatkowska, Monika, Sidhu, Sachdev S., D’Alessandro, Angelo, Catalano, Carlos E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2022
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9295703/
https://www.ncbi.nlm.nih.gov/pubmed/35796308
http://dx.doi.org/10.1021/acschembio.2c00256
_version_ 1784750105188892672
author McClary, Wynton D.
Catala, Alexis
Zhang, Wei
Gamboni, Fabia
Dzieciatkowska, Monika
Sidhu, Sachdev S.
D’Alessandro, Angelo
Catalano, Carlos E.
author_facet McClary, Wynton D.
Catala, Alexis
Zhang, Wei
Gamboni, Fabia
Dzieciatkowska, Monika
Sidhu, Sachdev S.
D’Alessandro, Angelo
Catalano, Carlos E.
author_sort McClary, Wynton D.
collection PubMed
description [Image: see text] Biological therapeutics represent an increasing and critical component of newly approved drugs; however, the inability to deliver biologics intracellularly in a controlled manner remains a major limitation. We have developed a semi-synthetic, tunable phage-like particle (PLP) platform derived from bacteriophage λ. The shell surface can be decorated with small-molecule, biological and synthetic moieties, alone or in combination and in defined ratios. Here, we demonstrate that the platform can be used to deliver biological macromolecules intracellularly and in a controlled manner. Ubiquitin-specific protease 7 (USP7) is a deubiquitinating enzyme that has been widely recognized as an ideal target for the treatment of a variety of cancers. Recently, UbV.7.2, a novel biologic derived from the ubiquitin scaffold, was developed for inhibition of USP7, but issues remain in achieving efficient and controlled intracellular delivery of the biologic. We have shown that decoration of PLPs with trastuzumab (Trz), a HER2-targeted therapeutic used in the treatment of various cancers, results in specific targeting and uptake of Trz-PLPs into HER2-overexpressing breast cancer cells. By simultaneously decorating PLPs with Trz and UbV.7.2, we now show that these particles are also internalized by HER2-positive cells, thus providing a means for intracellular delivery of the biologic in a controlled fashion. Internalized particles retain USP7 inhibition activity of UbV.7.2 and alter the metabolic and proteomic landscapes of these cells. This study demonstrates that the λ “designer nanoparticles” represent a powerful system for the intracellular delivery of biologics in a defined dose.
format Online
Article
Text
id pubmed-9295703
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher American Chemical Society
record_format MEDLINE/PubMed
spelling pubmed-92957032023-07-07 A Designer Nanoparticle Platform for Controlled Intracellular Delivery of Bioactive Macromolecules: Inhibition of Ubiquitin-Specific Protease 7 in Breast Cancer Cells McClary, Wynton D. Catala, Alexis Zhang, Wei Gamboni, Fabia Dzieciatkowska, Monika Sidhu, Sachdev S. D’Alessandro, Angelo Catalano, Carlos E. ACS Chem Biol [Image: see text] Biological therapeutics represent an increasing and critical component of newly approved drugs; however, the inability to deliver biologics intracellularly in a controlled manner remains a major limitation. We have developed a semi-synthetic, tunable phage-like particle (PLP) platform derived from bacteriophage λ. The shell surface can be decorated with small-molecule, biological and synthetic moieties, alone or in combination and in defined ratios. Here, we demonstrate that the platform can be used to deliver biological macromolecules intracellularly and in a controlled manner. Ubiquitin-specific protease 7 (USP7) is a deubiquitinating enzyme that has been widely recognized as an ideal target for the treatment of a variety of cancers. Recently, UbV.7.2, a novel biologic derived from the ubiquitin scaffold, was developed for inhibition of USP7, but issues remain in achieving efficient and controlled intracellular delivery of the biologic. We have shown that decoration of PLPs with trastuzumab (Trz), a HER2-targeted therapeutic used in the treatment of various cancers, results in specific targeting and uptake of Trz-PLPs into HER2-overexpressing breast cancer cells. By simultaneously decorating PLPs with Trz and UbV.7.2, we now show that these particles are also internalized by HER2-positive cells, thus providing a means for intracellular delivery of the biologic in a controlled fashion. Internalized particles retain USP7 inhibition activity of UbV.7.2 and alter the metabolic and proteomic landscapes of these cells. This study demonstrates that the λ “designer nanoparticles” represent a powerful system for the intracellular delivery of biologics in a defined dose. American Chemical Society 2022-07-07 2022-07-15 /pmc/articles/PMC9295703/ /pubmed/35796308 http://dx.doi.org/10.1021/acschembio.2c00256 Text en © 2022 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by-nc-nd/4.0/Permits non-commercial access and re-use, provided that author attribution and integrity are maintained; but does not permit creation of adaptations or other derivative works (https://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle McClary, Wynton D.
Catala, Alexis
Zhang, Wei
Gamboni, Fabia
Dzieciatkowska, Monika
Sidhu, Sachdev S.
D’Alessandro, Angelo
Catalano, Carlos E.
A Designer Nanoparticle Platform for Controlled Intracellular Delivery of Bioactive Macromolecules: Inhibition of Ubiquitin-Specific Protease 7 in Breast Cancer Cells
title A Designer Nanoparticle Platform for Controlled Intracellular Delivery of Bioactive Macromolecules: Inhibition of Ubiquitin-Specific Protease 7 in Breast Cancer Cells
title_full A Designer Nanoparticle Platform for Controlled Intracellular Delivery of Bioactive Macromolecules: Inhibition of Ubiquitin-Specific Protease 7 in Breast Cancer Cells
title_fullStr A Designer Nanoparticle Platform for Controlled Intracellular Delivery of Bioactive Macromolecules: Inhibition of Ubiquitin-Specific Protease 7 in Breast Cancer Cells
title_full_unstemmed A Designer Nanoparticle Platform for Controlled Intracellular Delivery of Bioactive Macromolecules: Inhibition of Ubiquitin-Specific Protease 7 in Breast Cancer Cells
title_short A Designer Nanoparticle Platform for Controlled Intracellular Delivery of Bioactive Macromolecules: Inhibition of Ubiquitin-Specific Protease 7 in Breast Cancer Cells
title_sort designer nanoparticle platform for controlled intracellular delivery of bioactive macromolecules: inhibition of ubiquitin-specific protease 7 in breast cancer cells
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9295703/
https://www.ncbi.nlm.nih.gov/pubmed/35796308
http://dx.doi.org/10.1021/acschembio.2c00256
work_keys_str_mv AT mcclarywyntond adesignernanoparticleplatformforcontrolledintracellulardeliveryofbioactivemacromoleculesinhibitionofubiquitinspecificprotease7inbreastcancercells
AT catalaalexis adesignernanoparticleplatformforcontrolledintracellulardeliveryofbioactivemacromoleculesinhibitionofubiquitinspecificprotease7inbreastcancercells
AT zhangwei adesignernanoparticleplatformforcontrolledintracellulardeliveryofbioactivemacromoleculesinhibitionofubiquitinspecificprotease7inbreastcancercells
AT gambonifabia adesignernanoparticleplatformforcontrolledintracellulardeliveryofbioactivemacromoleculesinhibitionofubiquitinspecificprotease7inbreastcancercells
AT dzieciatkowskamonika adesignernanoparticleplatformforcontrolledintracellulardeliveryofbioactivemacromoleculesinhibitionofubiquitinspecificprotease7inbreastcancercells
AT sidhusachdevs adesignernanoparticleplatformforcontrolledintracellulardeliveryofbioactivemacromoleculesinhibitionofubiquitinspecificprotease7inbreastcancercells
AT dalessandroangelo adesignernanoparticleplatformforcontrolledintracellulardeliveryofbioactivemacromoleculesinhibitionofubiquitinspecificprotease7inbreastcancercells
AT catalanocarlose adesignernanoparticleplatformforcontrolledintracellulardeliveryofbioactivemacromoleculesinhibitionofubiquitinspecificprotease7inbreastcancercells
AT mcclarywyntond designernanoparticleplatformforcontrolledintracellulardeliveryofbioactivemacromoleculesinhibitionofubiquitinspecificprotease7inbreastcancercells
AT catalaalexis designernanoparticleplatformforcontrolledintracellulardeliveryofbioactivemacromoleculesinhibitionofubiquitinspecificprotease7inbreastcancercells
AT zhangwei designernanoparticleplatformforcontrolledintracellulardeliveryofbioactivemacromoleculesinhibitionofubiquitinspecificprotease7inbreastcancercells
AT gambonifabia designernanoparticleplatformforcontrolledintracellulardeliveryofbioactivemacromoleculesinhibitionofubiquitinspecificprotease7inbreastcancercells
AT dzieciatkowskamonika designernanoparticleplatformforcontrolledintracellulardeliveryofbioactivemacromoleculesinhibitionofubiquitinspecificprotease7inbreastcancercells
AT sidhusachdevs designernanoparticleplatformforcontrolledintracellulardeliveryofbioactivemacromoleculesinhibitionofubiquitinspecificprotease7inbreastcancercells
AT dalessandroangelo designernanoparticleplatformforcontrolledintracellulardeliveryofbioactivemacromoleculesinhibitionofubiquitinspecificprotease7inbreastcancercells
AT catalanocarlose designernanoparticleplatformforcontrolledintracellulardeliveryofbioactivemacromoleculesinhibitionofubiquitinspecificprotease7inbreastcancercells