Cargando…
Designed ferritin nanocages displaying trimeric TRAIL and tumor-targeting peptides confer superior anti-tumor efficacy
TRAIL is considered a promising target for cancer therapy because it mediates activation of the extrinsic apoptosis pathway in a tumor-specific manner by binding to and trimerizing its functional receptors, DR4 or DR5. Although recombinant human TRAIL has shown high potency and specificity for killi...
Autores principales: | , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7672110/ https://www.ncbi.nlm.nih.gov/pubmed/33203916 http://dx.doi.org/10.1038/s41598-020-77095-x |
_version_ | 1783611062166224896 |
---|---|
author | Yoo, Jae Do Bae, Sang Mun Seo, Junyoung Jeon, In Seon Vadevoo, Sri Murugan Poongkavithai Kim, Sang-Yeob Kim, In-San Lee, Byungheon Kim, Soyoun |
author_facet | Yoo, Jae Do Bae, Sang Mun Seo, Junyoung Jeon, In Seon Vadevoo, Sri Murugan Poongkavithai Kim, Sang-Yeob Kim, In-San Lee, Byungheon Kim, Soyoun |
author_sort | Yoo, Jae Do |
collection | PubMed |
description | TRAIL is considered a promising target for cancer therapy because it mediates activation of the extrinsic apoptosis pathway in a tumor-specific manner by binding to and trimerizing its functional receptors, DR4 or DR5. Although recombinant human TRAIL has shown high potency and specificity for killing cancer cells in preclinical studies, it has failed in multiple clinical trials for several reasons, including a very short half-life mainly caused by instability of the monomeric form of TRAIL and rapid renal clearance of the off-targeted TRAIL. To overcome such obstacles, we developed a TRAIL-active trimer nanocage (TRAIL-ATNC) that presents the TRAIL ligand in its trimer-like conformation by connecting it to a triple helix sequence that links to the threefold axis of the ferritin nanocage. We also ligated the tumor-targeting peptide, IL4rP, to TRAIL-ATNC to enhance tumor targeting. The developed TRAIL-ATNC(IL4rP) showed enhanced agonistic activity compared with monomeric TRAIL. The in vivo serum half-life of TRAIL-ATNC(IL4rP) was ~ 16-times longer than that of native TRAIL. As a consequence of these properties, TRAIL-ATNC(IL4rP) exhibited efficacy as an anti-tumor agent in vivo against xenograft breast cancer as well as orthotopic pancreatic cancer models, highlighting the promise of this system for development as novel therapeutics against cancer. |
format | Online Article Text |
id | pubmed-7672110 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-76721102020-11-19 Designed ferritin nanocages displaying trimeric TRAIL and tumor-targeting peptides confer superior anti-tumor efficacy Yoo, Jae Do Bae, Sang Mun Seo, Junyoung Jeon, In Seon Vadevoo, Sri Murugan Poongkavithai Kim, Sang-Yeob Kim, In-San Lee, Byungheon Kim, Soyoun Sci Rep Article TRAIL is considered a promising target for cancer therapy because it mediates activation of the extrinsic apoptosis pathway in a tumor-specific manner by binding to and trimerizing its functional receptors, DR4 or DR5. Although recombinant human TRAIL has shown high potency and specificity for killing cancer cells in preclinical studies, it has failed in multiple clinical trials for several reasons, including a very short half-life mainly caused by instability of the monomeric form of TRAIL and rapid renal clearance of the off-targeted TRAIL. To overcome such obstacles, we developed a TRAIL-active trimer nanocage (TRAIL-ATNC) that presents the TRAIL ligand in its trimer-like conformation by connecting it to a triple helix sequence that links to the threefold axis of the ferritin nanocage. We also ligated the tumor-targeting peptide, IL4rP, to TRAIL-ATNC to enhance tumor targeting. The developed TRAIL-ATNC(IL4rP) showed enhanced agonistic activity compared with monomeric TRAIL. The in vivo serum half-life of TRAIL-ATNC(IL4rP) was ~ 16-times longer than that of native TRAIL. As a consequence of these properties, TRAIL-ATNC(IL4rP) exhibited efficacy as an anti-tumor agent in vivo against xenograft breast cancer as well as orthotopic pancreatic cancer models, highlighting the promise of this system for development as novel therapeutics against cancer. Nature Publishing Group UK 2020-11-17 /pmc/articles/PMC7672110/ /pubmed/33203916 http://dx.doi.org/10.1038/s41598-020-77095-x Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Yoo, Jae Do Bae, Sang Mun Seo, Junyoung Jeon, In Seon Vadevoo, Sri Murugan Poongkavithai Kim, Sang-Yeob Kim, In-San Lee, Byungheon Kim, Soyoun Designed ferritin nanocages displaying trimeric TRAIL and tumor-targeting peptides confer superior anti-tumor efficacy |
title | Designed ferritin nanocages displaying trimeric TRAIL and tumor-targeting peptides confer superior anti-tumor efficacy |
title_full | Designed ferritin nanocages displaying trimeric TRAIL and tumor-targeting peptides confer superior anti-tumor efficacy |
title_fullStr | Designed ferritin nanocages displaying trimeric TRAIL and tumor-targeting peptides confer superior anti-tumor efficacy |
title_full_unstemmed | Designed ferritin nanocages displaying trimeric TRAIL and tumor-targeting peptides confer superior anti-tumor efficacy |
title_short | Designed ferritin nanocages displaying trimeric TRAIL and tumor-targeting peptides confer superior anti-tumor efficacy |
title_sort | designed ferritin nanocages displaying trimeric trail and tumor-targeting peptides confer superior anti-tumor efficacy |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7672110/ https://www.ncbi.nlm.nih.gov/pubmed/33203916 http://dx.doi.org/10.1038/s41598-020-77095-x |
work_keys_str_mv | AT yoojaedo designedferritinnanocagesdisplayingtrimerictrailandtumortargetingpeptidesconfersuperiorantitumorefficacy AT baesangmun designedferritinnanocagesdisplayingtrimerictrailandtumortargetingpeptidesconfersuperiorantitumorefficacy AT seojunyoung designedferritinnanocagesdisplayingtrimerictrailandtumortargetingpeptidesconfersuperiorantitumorefficacy AT jeoninseon designedferritinnanocagesdisplayingtrimerictrailandtumortargetingpeptidesconfersuperiorantitumorefficacy AT vadevoosrimuruganpoongkavithai designedferritinnanocagesdisplayingtrimerictrailandtumortargetingpeptidesconfersuperiorantitumorefficacy AT kimsangyeob designedferritinnanocagesdisplayingtrimerictrailandtumortargetingpeptidesconfersuperiorantitumorefficacy AT kiminsan designedferritinnanocagesdisplayingtrimerictrailandtumortargetingpeptidesconfersuperiorantitumorefficacy AT leebyungheon designedferritinnanocagesdisplayingtrimerictrailandtumortargetingpeptidesconfersuperiorantitumorefficacy AT kimsoyoun designedferritinnanocagesdisplayingtrimerictrailandtumortargetingpeptidesconfersuperiorantitumorefficacy |