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Engineered vitamin E-tethered non-immunogenic facial lipopeptide for developing improved siRNA based combination therapy against metastatic breast cancer
RNA interference based therapeutic gene silencing is an emerging platform for managing highly metastatic breast cancer. Cytosolic delivery of functional siRNA remains the key obstacle for efficient RNAi therapy. To overcome the challenges of siRNA delivery, we have engineered a vitamin E-tethered, s...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Royal Society of Chemistry
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10370593/ https://www.ncbi.nlm.nih.gov/pubmed/37502330 http://dx.doi.org/10.1039/d3sc01071f |
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author | Mallick, Argha Mario Biswas, Abhijit Mishra, Sukumar Jadhav, Sonali Chakraborty, Kasturee Tripathi, Archana Mukherjee, Arnab Roy, Rituparna Sinha |
author_facet | Mallick, Argha Mario Biswas, Abhijit Mishra, Sukumar Jadhav, Sonali Chakraborty, Kasturee Tripathi, Archana Mukherjee, Arnab Roy, Rituparna Sinha |
author_sort | Mallick, Argha Mario |
collection | PubMed |
description | RNA interference based therapeutic gene silencing is an emerging platform for managing highly metastatic breast cancer. Cytosolic delivery of functional siRNA remains the key obstacle for efficient RNAi therapy. To overcome the challenges of siRNA delivery, we have engineered a vitamin E-tethered, short, optimum protease stabilized facial lipopeptide based non-immunogenic, biocompatible siRNA transporter to facilitate the clinical translation in future. Our designed lipopeptide has an Arginine-Sarcosine-Arginine segment for providing optimum protease-stability, minimizing adjacent arginine–arginine repulsion and reducing intermolecular aggregation and α-tocopherol as the lipidic moiety for facilitating cellular permeabilization. Interestingly, our designed non-immunogenic siRNA transporter has exhibited significantly better long term transfection efficiency than HiPerFect and can transfect hard to transfect primary cell line, HUVEC. Our engineered siRNA therapeutics demonstrated high efficacy in managing metastasis against triple negative breast cancer by disrupting the crosstalk of endothelial cells and MDA-MB-231 and reduced stemness and metastatic markers, as evidenced by downregulating critical oncogenic pathways. Our study aimed at silencing Notch1 signalling to achieve “multi-targeted” therapy with a single putative molecular medicine. We have further developed mechanistically rational combination therapy combining Notch1 silencing with a repurposed drug m-TOR inhibitor, metformin, which demonstrated synergistic interaction and enhanced antitumor efficacy against cancer metastasis. |
format | Online Article Text |
id | pubmed-10370593 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | The Royal Society of Chemistry |
record_format | MEDLINE/PubMed |
spelling | pubmed-103705932023-07-27 Engineered vitamin E-tethered non-immunogenic facial lipopeptide for developing improved siRNA based combination therapy against metastatic breast cancer Mallick, Argha Mario Biswas, Abhijit Mishra, Sukumar Jadhav, Sonali Chakraborty, Kasturee Tripathi, Archana Mukherjee, Arnab Roy, Rituparna Sinha Chem Sci Chemistry RNA interference based therapeutic gene silencing is an emerging platform for managing highly metastatic breast cancer. Cytosolic delivery of functional siRNA remains the key obstacle for efficient RNAi therapy. To overcome the challenges of siRNA delivery, we have engineered a vitamin E-tethered, short, optimum protease stabilized facial lipopeptide based non-immunogenic, biocompatible siRNA transporter to facilitate the clinical translation in future. Our designed lipopeptide has an Arginine-Sarcosine-Arginine segment for providing optimum protease-stability, minimizing adjacent arginine–arginine repulsion and reducing intermolecular aggregation and α-tocopherol as the lipidic moiety for facilitating cellular permeabilization. Interestingly, our designed non-immunogenic siRNA transporter has exhibited significantly better long term transfection efficiency than HiPerFect and can transfect hard to transfect primary cell line, HUVEC. Our engineered siRNA therapeutics demonstrated high efficacy in managing metastasis against triple negative breast cancer by disrupting the crosstalk of endothelial cells and MDA-MB-231 and reduced stemness and metastatic markers, as evidenced by downregulating critical oncogenic pathways. Our study aimed at silencing Notch1 signalling to achieve “multi-targeted” therapy with a single putative molecular medicine. We have further developed mechanistically rational combination therapy combining Notch1 silencing with a repurposed drug m-TOR inhibitor, metformin, which demonstrated synergistic interaction and enhanced antitumor efficacy against cancer metastasis. The Royal Society of Chemistry 2023-07-03 /pmc/articles/PMC10370593/ /pubmed/37502330 http://dx.doi.org/10.1039/d3sc01071f Text en This journal is © The Royal Society of Chemistry https://creativecommons.org/licenses/by-nc/3.0/ |
spellingShingle | Chemistry Mallick, Argha Mario Biswas, Abhijit Mishra, Sukumar Jadhav, Sonali Chakraborty, Kasturee Tripathi, Archana Mukherjee, Arnab Roy, Rituparna Sinha Engineered vitamin E-tethered non-immunogenic facial lipopeptide for developing improved siRNA based combination therapy against metastatic breast cancer |
title | Engineered vitamin E-tethered non-immunogenic facial lipopeptide for developing improved siRNA based combination therapy against metastatic breast cancer |
title_full | Engineered vitamin E-tethered non-immunogenic facial lipopeptide for developing improved siRNA based combination therapy against metastatic breast cancer |
title_fullStr | Engineered vitamin E-tethered non-immunogenic facial lipopeptide for developing improved siRNA based combination therapy against metastatic breast cancer |
title_full_unstemmed | Engineered vitamin E-tethered non-immunogenic facial lipopeptide for developing improved siRNA based combination therapy against metastatic breast cancer |
title_short | Engineered vitamin E-tethered non-immunogenic facial lipopeptide for developing improved siRNA based combination therapy against metastatic breast cancer |
title_sort | engineered vitamin e-tethered non-immunogenic facial lipopeptide for developing improved sirna based combination therapy against metastatic breast cancer |
topic | Chemistry |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10370593/ https://www.ncbi.nlm.nih.gov/pubmed/37502330 http://dx.doi.org/10.1039/d3sc01071f |
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