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Hyaluronic Acid-Functionalized Nanomicelles Enhance SAHA Efficacy in 3D Endometrial Cancer Models

Kadie Edwards Orcid Logo, Seydou Yao, Simone Pisano, Veronica Feltracco, Katja Bruesehafer, Sumanta Samanta, Oommen P. Oommen, Salvatore Gazze, Roberta Paravati, Holly Maddison, Chao Li, Deya Gonzalez Orcid Logo, Steve Conlan Orcid Logo, Lewis Francis Orcid Logo

Cancers, Volume: 13, Issue: 16, Start page: 4032

Swansea University Authors: Kadie Edwards Orcid Logo, Seydou Yao, Simone Pisano, Veronica Feltracco, Katja Bruesehafer, Salvatore Gazze, Deya Gonzalez Orcid Logo, Steve Conlan Orcid Logo, Lewis Francis Orcid Logo

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DOI (Published version): 10.3390/cancers13164032

Abstract

Histone Deacetylase (HDAC) enzymes are upregulated in cancer leading to the development of HDAC inhibiting compounds, several of which are currently in clinical trials. Side effects associated with toxicity and non-specific targeting indicate the need for efficient drug delivery approaches and tumor...

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Published in: Cancers
ISSN: 2072-6694
Published: MDPI AG 2021
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Side effects associated with toxicity and non-specific targeting indicate the need for efficient drug delivery approaches and tumor specific targeting to enhance HDAC efficacy in solid tumor cancers. SAHA encapsulation within F127 micelles functionalized with a surface hyaluronic acid moiety, was developed to target endometrial cancer cells expressing elevated levels of CD44. In vitro viability and morphology analyses was conducted in both 2D and 3D models to assess the translational potential of this approach. Encapsulation enhanced SAHA delivery and activity, demonstrating increased cytotoxic efficacy in 2D and 3D endometrial cancer models. High-content imaging showed improved nanoparticle internalization in 2D and CD44 enhanced penetration in 3D models. In addition, the nano-delivery system enhanced spheroid penetration resulting in cell growth suppression, p21 associated cell cycle arrest, as well as overcoming the formation of an EMT associated phenotype observed in free drug treated type II endometrial cancer cells. This study demonstrates that targeted nanoparticle delivery of SAHA could provide the basis for improving its efficacy in endometrial cancer. 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spelling 2022-10-25T16:25:12.7592456 v2 57595 2021-08-10 Hyaluronic Acid-Functionalized Nanomicelles Enhance SAHA Efficacy in 3D Endometrial Cancer Models 76d053c090d5064ae9558888f7985e92 0000-0002-1359-0359 Kadie Edwards Kadie Edwards true false b5e52476f454ce031a48e57680ee10e0 Seydou Yao Seydou Yao true false 4c4284743c846288b5a5312d3d49464b Simone Pisano Simone Pisano true false b35b908a1fc4e192a159855cfcb52126 Veronica Feltracco Veronica Feltracco true false 4362be1f5c0cd447b9d775355b145b07 Katja Bruesehafer Katja Bruesehafer true false 586f1f49652b97c5c3ab99a45a1c58bf Salvatore Gazze Salvatore Gazze true false bafdf635eb81280304eedf4b18e65d4e 0000-0002-1838-6752 Deya Gonzalez Deya Gonzalez true false 0bb6bd247e32fb4249de62c0013b51cb 0000-0002-2562-3461 Steve Conlan Steve Conlan true false 10f61f9c1248951c1a33f6a89498f37d 0000-0002-7803-7714 Lewis Francis Lewis Francis true false 2021-08-10 BMS Histone Deacetylase (HDAC) enzymes are upregulated in cancer leading to the development of HDAC inhibiting compounds, several of which are currently in clinical trials. Side effects associated with toxicity and non-specific targeting indicate the need for efficient drug delivery approaches and tumor specific targeting to enhance HDAC efficacy in solid tumor cancers. SAHA encapsulation within F127 micelles functionalized with a surface hyaluronic acid moiety, was developed to target endometrial cancer cells expressing elevated levels of CD44. In vitro viability and morphology analyses was conducted in both 2D and 3D models to assess the translational potential of this approach. Encapsulation enhanced SAHA delivery and activity, demonstrating increased cytotoxic efficacy in 2D and 3D endometrial cancer models. High-content imaging showed improved nanoparticle internalization in 2D and CD44 enhanced penetration in 3D models. In addition, the nano-delivery system enhanced spheroid penetration resulting in cell growth suppression, p21 associated cell cycle arrest, as well as overcoming the formation of an EMT associated phenotype observed in free drug treated type II endometrial cancer cells. This study demonstrates that targeted nanoparticle delivery of SAHA could provide the basis for improving its efficacy in endometrial cancer. Using 3D models for endometrial cancer allows the elucidation of nanoparticle performance and CD44 targeting, likely through penetration and retention within the tumor model. Journal Article Cancers 13 16 4032 MDPI AG 2072-6694 polymeric nanoparticles; hyaluronic acid; epigenetics; SAHA; nanomedicines; gynecological oncology; F127 micelles; targeted therapeutics; 3D models 10 8 2021 2021-08-10 10.3390/cancers13164032 COLLEGE NANME Biomedical Sciences COLLEGE CODE BMS Swansea University Other This research was funded by Welsh Government’s European Social Fund (ESF) convergence programme for West Wales and the Valleys KESS II and Tenovus Cancer Care (KE). The Celtic Advanced Life Science Innovation Network (CALIN), an Ireland Wales 2014–2020 programme part funded by the European Regional Development Fund through the Welsh Government (SY). The Erasmus+ Mobility Scheme (SP), this project was co-funded by the European Union. The Life Sciences Cancers 2021, 13, 4032 20 of 23 Research Network Wales: project grant ‘Nanoparticle delivery of epigenetic modifiers: a targeted approach for Endometrial Cancer treatment’ (KB). The Natural and Environmental Research Council, UK [grant number NE/K004212/1] and SMARTExpertise 2014–2020 West Wales and the Valleys, European Regional Development Fund, under Grants 2017/COL/001 and 2017/COL/004 (AG). 2022-10-25T16:25:12.7592456 2021-08-10T18:55:09.0210710 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Kadie Edwards 0000-0002-1359-0359 1 Seydou Yao 2 Simone Pisano 3 Veronica Feltracco 4 Katja Bruesehafer 5 Sumanta Samanta 6 Oommen P. Oommen 7 Salvatore Gazze 8 Roberta Paravati 9 Holly Maddison 10 Chao Li 11 Deya Gonzalez 0000-0002-1838-6752 12 Steve Conlan 0000-0002-2562-3461 13 Lewis Francis 0000-0002-7803-7714 14 57595__20664__7fd0d97b75bb4e4cb934d18cba40b20e.pdf 57595.pdf 2021-08-18T15:23:15.1629048 Output 3464472 application/pdf Version of Record true Copyright: © 2021 by the authors. This is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license true eng https://creativecommons.org/licenses/by/4.0/
title Hyaluronic Acid-Functionalized Nanomicelles Enhance SAHA Efficacy in 3D Endometrial Cancer Models
spellingShingle Hyaluronic Acid-Functionalized Nanomicelles Enhance SAHA Efficacy in 3D Endometrial Cancer Models
Kadie Edwards
Seydou Yao
Simone Pisano
Veronica Feltracco
Katja Bruesehafer
Salvatore Gazze
Deya Gonzalez
Steve Conlan
Lewis Francis
title_short Hyaluronic Acid-Functionalized Nanomicelles Enhance SAHA Efficacy in 3D Endometrial Cancer Models
title_full Hyaluronic Acid-Functionalized Nanomicelles Enhance SAHA Efficacy in 3D Endometrial Cancer Models
title_fullStr Hyaluronic Acid-Functionalized Nanomicelles Enhance SAHA Efficacy in 3D Endometrial Cancer Models
title_full_unstemmed Hyaluronic Acid-Functionalized Nanomicelles Enhance SAHA Efficacy in 3D Endometrial Cancer Models
title_sort Hyaluronic Acid-Functionalized Nanomicelles Enhance SAHA Efficacy in 3D Endometrial Cancer Models
author_id_str_mv 76d053c090d5064ae9558888f7985e92
b5e52476f454ce031a48e57680ee10e0
4c4284743c846288b5a5312d3d49464b
b35b908a1fc4e192a159855cfcb52126
4362be1f5c0cd447b9d775355b145b07
586f1f49652b97c5c3ab99a45a1c58bf
bafdf635eb81280304eedf4b18e65d4e
0bb6bd247e32fb4249de62c0013b51cb
10f61f9c1248951c1a33f6a89498f37d
author_id_fullname_str_mv 76d053c090d5064ae9558888f7985e92_***_Kadie Edwards
b5e52476f454ce031a48e57680ee10e0_***_Seydou Yao
4c4284743c846288b5a5312d3d49464b_***_Simone Pisano
b35b908a1fc4e192a159855cfcb52126_***_Veronica Feltracco
4362be1f5c0cd447b9d775355b145b07_***_Katja Bruesehafer
586f1f49652b97c5c3ab99a45a1c58bf_***_Salvatore Gazze
bafdf635eb81280304eedf4b18e65d4e_***_Deya Gonzalez
0bb6bd247e32fb4249de62c0013b51cb_***_Steve Conlan
10f61f9c1248951c1a33f6a89498f37d_***_Lewis Francis
author Kadie Edwards
Seydou Yao
Simone Pisano
Veronica Feltracco
Katja Bruesehafer
Salvatore Gazze
Deya Gonzalez
Steve Conlan
Lewis Francis
author2 Kadie Edwards
Seydou Yao
Simone Pisano
Veronica Feltracco
Katja Bruesehafer
Sumanta Samanta
Oommen P. Oommen
Salvatore Gazze
Roberta Paravati
Holly Maddison
Chao Li
Deya Gonzalez
Steve Conlan
Lewis Francis
format Journal article
container_title Cancers
container_volume 13
container_issue 16
container_start_page 4032
publishDate 2021
institution Swansea University
issn 2072-6694
doi_str_mv 10.3390/cancers13164032
publisher MDPI AG
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
document_store_str 1
active_str 0
description Histone Deacetylase (HDAC) enzymes are upregulated in cancer leading to the development of HDAC inhibiting compounds, several of which are currently in clinical trials. Side effects associated with toxicity and non-specific targeting indicate the need for efficient drug delivery approaches and tumor specific targeting to enhance HDAC efficacy in solid tumor cancers. SAHA encapsulation within F127 micelles functionalized with a surface hyaluronic acid moiety, was developed to target endometrial cancer cells expressing elevated levels of CD44. In vitro viability and morphology analyses was conducted in both 2D and 3D models to assess the translational potential of this approach. Encapsulation enhanced SAHA delivery and activity, demonstrating increased cytotoxic efficacy in 2D and 3D endometrial cancer models. High-content imaging showed improved nanoparticle internalization in 2D and CD44 enhanced penetration in 3D models. In addition, the nano-delivery system enhanced spheroid penetration resulting in cell growth suppression, p21 associated cell cycle arrest, as well as overcoming the formation of an EMT associated phenotype observed in free drug treated type II endometrial cancer cells. This study demonstrates that targeted nanoparticle delivery of SAHA could provide the basis for improving its efficacy in endometrial cancer. Using 3D models for endometrial cancer allows the elucidation of nanoparticle performance and CD44 targeting, likely through penetration and retention within the tumor model.
published_date 2021-08-10T04:13:27Z
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score 11.013731

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