Staff View: Pre- and Post-Transcriptional Regulation of cFLIP for Effective Cancer Therapy Using pH-Ultrasensitive Nanoparticles

Pre- and Post-Transcriptional Regulation of cFLIP for Effective Cancer Therapy Using pH-Ultrasensitive Nanoparticles

Cellular FLIP (cFLIP) is a crucial player of apoptosis-regulated pathways that is frequently overexpressed in solid cancers. To inhibit c-FLIP, pre- and post-transcriptionally, a multifunctional nanoparticle (NP) was created to deliver cFLIP-specific small interfering RNA (siRNA) into cancer cells....

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Main Authors:	Phung, Cao Dai, Tran, Tuan Hiep, Choi, Ju-Yeon, Jeong, Jee-Heon, Ku, Sae Kwang, Yong, Chul Soon, Kim, Jong Oh
Format:	Article
Language:	English
Published:	ACS Appl. Mater. Interfaces 2021 2021
Subjects:	Effective Cancer Therapy pH-Ultrasensitive Nanoparticles
Online Access:	https://pubs.acs.org/doi/10.1021/acsami.0c20624 https://dlib.phenikaa-uni.edu.vn/handle/PNK/1427
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spelling	oai:localhost:PNK-14272022-08-17T05:54:40Z Pre- and Post-Transcriptional Regulation of cFLIP for Effective Cancer Therapy Using pH-Ultrasensitive Nanoparticles Phung, Cao Dai Tran, Tuan Hiep Choi, Ju-Yeon Jeong, Jee-Heon Ku, Sae Kwang Yong, Chul Soon Kim, Jong Oh Effective Cancer Therapy pH-Ultrasensitive Nanoparticles Cellular FLIP (cFLIP) is a crucial player of apoptosis-regulated pathways that is frequently overexpressed in solid cancers. To inhibit c-FLIP, pre- and post-transcriptionally, a multifunctional nanoparticle (NP) was created to deliver cFLIP-specific small interfering RNA (siRNA) into cancer cells. Specifically, Vorinostat (Vor)-loaded mesoporous silica nanoparticles (MSN) were conjugated with polyethylenimine-biotin (PB), followed by electrostatically binding with cFLIP siRNA (Vor/siR@MSN-PB). To stabilize and prolong the circulation time of nanoparticles, a bialdehyde-modified poly(ethylene glycol) (PEG) was cross-linked onto the polyethylenimine (PEI) backbone via the formation of the imine linkage (Schiff base) (Vor/siR@MSN-PB-PEG). The Schiff base is highly stable at physiological pH 7.4 but labile under slightly acidic pH conditions. In the acidic tumor microenvironment (TME), the PEG outer layer could be rapidly cleaved, resulting in the switching of the nanoparticle surface charge to positive, which specifically enhances internalization of the NPs to the biotin-positive tumor cells. Our results demonstrated the successful preparation of Vor/siR@MSN-PB-PEG NPs, in which the siRNA was effectively protected in serum and regulated the expression of cFlip, post-transcriptionally. The presence of the PEG layer resulted in high tumor accumulation and high efficacy in tumor inhibition, which was a result of the efficient cFLIP suppression. Furthermore, in the low-dose regimen of Vorinostat—the pre-transcriptional cFLIP suppressor, treatment with Vor/siR@MSN-PB-PEG NPs was found to be safe with the treated mice, indicating a promising combination regimen for cancer therapy. 2021-05-31T07:38:33Z 2021-05-31T07:38:33Z 2021 Article Working Paper https://pubs.acs.org/doi/10.1021/acsami.0c20624 https://dlib.phenikaa-uni.edu.vn/handle/PNK/1427 en application/pdf ACS Appl. Mater. Interfaces 2021
institution	Digital Phenikaa
collection	Digital Phenikaa
language	English
topic	Effective Cancer Therapy pH-Ultrasensitive Nanoparticles
spellingShingle	Effective Cancer Therapy pH-Ultrasensitive Nanoparticles Phung, Cao Dai Tran, Tuan Hiep Choi, Ju-Yeon Jeong, Jee-Heon Ku, Sae Kwang Yong, Chul Soon Kim, Jong Oh Pre- and Post-Transcriptional Regulation of cFLIP for Effective Cancer Therapy Using pH-Ultrasensitive Nanoparticles
description	Cellular FLIP (cFLIP) is a crucial player of apoptosis-regulated pathways that is frequently overexpressed in solid cancers. To inhibit c-FLIP, pre- and post-transcriptionally, a multifunctional nanoparticle (NP) was created to deliver cFLIP-specific small interfering RNA (siRNA) into cancer cells. Specifically, Vorinostat (Vor)-loaded mesoporous silica nanoparticles (MSN) were conjugated with polyethylenimine-biotin (PB), followed by electrostatically binding with cFLIP siRNA (Vor/siR@MSN-PB). To stabilize and prolong the circulation time of nanoparticles, a bialdehyde-modified poly(ethylene glycol) (PEG) was cross-linked onto the polyethylenimine (PEI) backbone via the formation of the imine linkage (Schiff base) (Vor/siR@MSN-PB-PEG). The Schiff base is highly stable at physiological pH 7.4 but labile under slightly acidic pH conditions. In the acidic tumor microenvironment (TME), the PEG outer layer could be rapidly cleaved, resulting in the switching of the nanoparticle surface charge to positive, which specifically enhances internalization of the NPs to the biotin-positive tumor cells. Our results demonstrated the successful preparation of Vor/siR@MSN-PB-PEG NPs, in which the siRNA was effectively protected in serum and regulated the expression of cFlip, post-transcriptionally. The presence of the PEG layer resulted in high tumor accumulation and high efficacy in tumor inhibition, which was a result of the efficient cFLIP suppression. Furthermore, in the low-dose regimen of Vorinostat—the pre-transcriptional cFLIP suppressor, treatment with Vor/siR@MSN-PB-PEG NPs was found to be safe with the treated mice, indicating a promising combination regimen for cancer therapy.
format	Article
author	Phung, Cao Dai Tran, Tuan Hiep Choi, Ju-Yeon Jeong, Jee-Heon Ku, Sae Kwang Yong, Chul Soon Kim, Jong Oh
author_facet	Phung, Cao Dai Tran, Tuan Hiep Choi, Ju-Yeon Jeong, Jee-Heon Ku, Sae Kwang Yong, Chul Soon Kim, Jong Oh
author_sort	Phung, Cao Dai
title	Pre- and Post-Transcriptional Regulation of cFLIP for Effective Cancer Therapy Using pH-Ultrasensitive Nanoparticles
title_short	Pre- and Post-Transcriptional Regulation of cFLIP for Effective Cancer Therapy Using pH-Ultrasensitive Nanoparticles
title_full	Pre- and Post-Transcriptional Regulation of cFLIP for Effective Cancer Therapy Using pH-Ultrasensitive Nanoparticles
title_fullStr	Pre- and Post-Transcriptional Regulation of cFLIP for Effective Cancer Therapy Using pH-Ultrasensitive Nanoparticles
title_full_unstemmed	Pre- and Post-Transcriptional Regulation of cFLIP for Effective Cancer Therapy Using pH-Ultrasensitive Nanoparticles
title_sort	pre- and post-transcriptional regulation of cflip for effective cancer therapy using ph-ultrasensitive nanoparticles
publisher	ACS Appl. Mater. Interfaces 2021
publishDate	2021
url	https://pubs.acs.org/doi/10.1021/acsami.0c20624 https://dlib.phenikaa-uni.edu.vn/handle/PNK/1427
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score	8.891145

Pre- and Post-Transcriptional Regulation of cFLIP for Effective Cancer Therapy Using pH-Ultrasensitive Nanoparticles

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