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Complement-Mediated Selective Tumor Cell Lysis Enabled by Bi-Functional RNA Aptamers

Unlike microbes that infect the human body, cancer cells are descended from normal cells and are not easily recognizable as “foreign” by the immune system of the host. However, if the malignant cells can be specifically earmarked for attack by a synthetic “designator”, the powerful effector mechanis...

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Detalles Bibliográficos
Autores principales: Mallik, Prabhat K., Nishikawa, Kimi, Mallik, Pramit, Shi, Hua
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8775132/
https://www.ncbi.nlm.nih.gov/pubmed/35052426
http://dx.doi.org/10.3390/genes13010086
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author Mallik, Prabhat K.
Nishikawa, Kimi
Mallik, Pramit
Shi, Hua
author_facet Mallik, Prabhat K.
Nishikawa, Kimi
Mallik, Pramit
Shi, Hua
author_sort Mallik, Prabhat K.
collection PubMed
description Unlike microbes that infect the human body, cancer cells are descended from normal cells and are not easily recognizable as “foreign” by the immune system of the host. However, if the malignant cells can be specifically earmarked for attack by a synthetic “designator”, the powerful effector mechanisms of the immune response can be conscripted to treat cancer. To implement this strategy, we have been developing aptamer-derived molecular adaptors to invoke synthetic immune responses against cancer cells. Here we describe multi-valent aptamers that simultaneously bind target molecules on the surface of cancer cells and an activated complement protein, which would tag the target molecules and their associated cells as “foreign” and trigger multiple effector mechanisms. Increased deposition of the complement proteins on the surface of cancer cells via aptamer binding to membrane targets could induce the formation of the membrane attack complex or cytotoxic degranulation by phagocytes and natural killer cells, thereby causing irreversible destruction of the targeted cells. Specifically, we designed and constructed a bi-functional aptamer linking EGFR and C3b/iC3b, and used it in a cell-based assay to cause lysis of MDA-MB-231 and BT-20 breast cancer cells, with either human or mouse serum as the source of complement factors.
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spelling pubmed-87751322022-01-21 Complement-Mediated Selective Tumor Cell Lysis Enabled by Bi-Functional RNA Aptamers Mallik, Prabhat K. Nishikawa, Kimi Mallik, Pramit Shi, Hua Genes (Basel) Article Unlike microbes that infect the human body, cancer cells are descended from normal cells and are not easily recognizable as “foreign” by the immune system of the host. However, if the malignant cells can be specifically earmarked for attack by a synthetic “designator”, the powerful effector mechanisms of the immune response can be conscripted to treat cancer. To implement this strategy, we have been developing aptamer-derived molecular adaptors to invoke synthetic immune responses against cancer cells. Here we describe multi-valent aptamers that simultaneously bind target molecules on the surface of cancer cells and an activated complement protein, which would tag the target molecules and their associated cells as “foreign” and trigger multiple effector mechanisms. Increased deposition of the complement proteins on the surface of cancer cells via aptamer binding to membrane targets could induce the formation of the membrane attack complex or cytotoxic degranulation by phagocytes and natural killer cells, thereby causing irreversible destruction of the targeted cells. Specifically, we designed and constructed a bi-functional aptamer linking EGFR and C3b/iC3b, and used it in a cell-based assay to cause lysis of MDA-MB-231 and BT-20 breast cancer cells, with either human or mouse serum as the source of complement factors. MDPI 2021-12-29 /pmc/articles/PMC8775132/ /pubmed/35052426 http://dx.doi.org/10.3390/genes13010086 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Mallik, Prabhat K.
Nishikawa, Kimi
Mallik, Pramit
Shi, Hua
Complement-Mediated Selective Tumor Cell Lysis Enabled by Bi-Functional RNA Aptamers
title Complement-Mediated Selective Tumor Cell Lysis Enabled by Bi-Functional RNA Aptamers
title_full Complement-Mediated Selective Tumor Cell Lysis Enabled by Bi-Functional RNA Aptamers
title_fullStr Complement-Mediated Selective Tumor Cell Lysis Enabled by Bi-Functional RNA Aptamers
title_full_unstemmed Complement-Mediated Selective Tumor Cell Lysis Enabled by Bi-Functional RNA Aptamers
title_short Complement-Mediated Selective Tumor Cell Lysis Enabled by Bi-Functional RNA Aptamers
title_sort complement-mediated selective tumor cell lysis enabled by bi-functional rna aptamers
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8775132/
https://www.ncbi.nlm.nih.gov/pubmed/35052426
http://dx.doi.org/10.3390/genes13010086
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