Internalization of Foldamer-Based DNA Mimics through a Site-Specific Antibody Conjugate to Target HER2-Positive Cancer Cells
Inhibition of protein–DNA interactions represents an attractive strategy to modulate essential cellular functions. We reported the synthesis of unique oligoamide-based foldamers that adopt single helical conformations and mimic the negatively charged phosphate moieties of B-DNA. These mimics alter t...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-06-01
|
| Series: | Pharmaceuticals |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1424-8247/14/7/624 |
| _version_ | 1797528556965724160 |
|---|---|
| author | Valentina Corvaglia Imène Ait Mohamed Amar Véronique Garambois Stéphanie Letast Aurélie Garcin Céline Gongora Maguy Del Rio Caroline Denevault-Sabourin Nicolas Joubert Ivan Huc Philippe Pourquier |
| author_facet | Valentina Corvaglia Imène Ait Mohamed Amar Véronique Garambois Stéphanie Letast Aurélie Garcin Céline Gongora Maguy Del Rio Caroline Denevault-Sabourin Nicolas Joubert Ivan Huc Philippe Pourquier |
| author_sort | Valentina Corvaglia |
| collection | DOAJ |
| description | Inhibition of protein–DNA interactions represents an attractive strategy to modulate essential cellular functions. We reported the synthesis of unique oligoamide-based foldamers that adopt single helical conformations and mimic the negatively charged phosphate moieties of B-DNA. These mimics alter the activity of DNA interacting enzymes used as targets for cancer treatment, such as DNA topoisomerase I, and they are cytotoxic only in the presence of a transfection agent. The aim of our study was to improve internalization and selective delivery of these highly charged molecules to cancer cells. For this purpose, we synthesized an antibody-drug conjugate (ADC) using a DNA mimic as a payload to specifically target cancer cells overexpressing HER2. We report the bioconjugation of a 16-mer DNA mimic with trastuzumab and its functional validation in breast and ovarian cancer cells expressing various levels of HER2. Binding of the ADC to HER2 increased with the expression of the receptor. The ADC was internalized into cells and was more efficient than trastuzumab at inhibiting their growth in vitro. These results provide proof of concept that it is possible to site-specifically graft high molecular weight payloads such as DNA mimics onto monoclonal antibodies to improve their selective internalization and delivery in cancer cells. |
| first_indexed | 2024-03-10T10:00:01Z |
| format | Article |
| id | doaj.art-cf02bd029f4647c98225f8673b64d484 |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-10T10:00:01Z |
| publishDate | 2021-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-cf02bd029f4647c98225f8673b64d4842023-11-22T02:02:46ZengMDPI AGPharmaceuticals1424-82472021-06-0114762410.3390/ph14070624Internalization of Foldamer-Based DNA Mimics through a Site-Specific Antibody Conjugate to Target HER2-Positive Cancer CellsValentina Corvaglia0Imène Ait Mohamed Amar1Véronique Garambois2Stéphanie Letast3Aurélie Garcin4Céline Gongora5Maguy Del Rio6Caroline Denevault-Sabourin7Nicolas Joubert8Ivan Huc9Philippe Pourquier10Center for Integrated Protein Science, Department of Pharmacy, Ludwig-Maximilians-Universität, 81377 Munich, GermanyGICC EA7501, Equipe IMT, Université de Tours, 10 Boulevard Tonnellé, F-37032 Tours, FranceInstitut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université de Montpellier, F-34298 Montpellier, FranceGICC EA7501, Equipe IMT, Université de Tours, 10 Boulevard Tonnellé, F-37032 Tours, FranceInstitut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université de Montpellier, F-34298 Montpellier, FranceInstitut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université de Montpellier, F-34298 Montpellier, FranceInstitut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université de Montpellier, F-34298 Montpellier, FranceGICC EA7501, Equipe IMT, Université de Tours, 10 Boulevard Tonnellé, F-37032 Tours, FranceGICC EA7501, Equipe IMT, Université de Tours, 10 Boulevard Tonnellé, F-37032 Tours, FranceCenter for Integrated Protein Science, Department of Pharmacy, Ludwig-Maximilians-Universität, 81377 Munich, GermanyInstitut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université de Montpellier, F-34298 Montpellier, FranceInhibition of protein–DNA interactions represents an attractive strategy to modulate essential cellular functions. We reported the synthesis of unique oligoamide-based foldamers that adopt single helical conformations and mimic the negatively charged phosphate moieties of B-DNA. These mimics alter the activity of DNA interacting enzymes used as targets for cancer treatment, such as DNA topoisomerase I, and they are cytotoxic only in the presence of a transfection agent. The aim of our study was to improve internalization and selective delivery of these highly charged molecules to cancer cells. For this purpose, we synthesized an antibody-drug conjugate (ADC) using a DNA mimic as a payload to specifically target cancer cells overexpressing HER2. We report the bioconjugation of a 16-mer DNA mimic with trastuzumab and its functional validation in breast and ovarian cancer cells expressing various levels of HER2. Binding of the ADC to HER2 increased with the expression of the receptor. The ADC was internalized into cells and was more efficient than trastuzumab at inhibiting their growth in vitro. These results provide proof of concept that it is possible to site-specifically graft high molecular weight payloads such as DNA mimics onto monoclonal antibodies to improve their selective internalization and delivery in cancer cells.https://www.mdpi.com/1424-8247/14/7/624DNA mimicsfoldamerantibody-drug conjugatetrastuzumabHER2 |
| spellingShingle | Valentina Corvaglia Imène Ait Mohamed Amar Véronique Garambois Stéphanie Letast Aurélie Garcin Céline Gongora Maguy Del Rio Caroline Denevault-Sabourin Nicolas Joubert Ivan Huc Philippe Pourquier Internalization of Foldamer-Based DNA Mimics through a Site-Specific Antibody Conjugate to Target HER2-Positive Cancer Cells Pharmaceuticals DNA mimics foldamer antibody-drug conjugate trastuzumab HER2 |
| title | Internalization of Foldamer-Based DNA Mimics through a Site-Specific Antibody Conjugate to Target HER2-Positive Cancer Cells |
| title_full | Internalization of Foldamer-Based DNA Mimics through a Site-Specific Antibody Conjugate to Target HER2-Positive Cancer Cells |
| title_fullStr | Internalization of Foldamer-Based DNA Mimics through a Site-Specific Antibody Conjugate to Target HER2-Positive Cancer Cells |
| title_full_unstemmed | Internalization of Foldamer-Based DNA Mimics through a Site-Specific Antibody Conjugate to Target HER2-Positive Cancer Cells |
| title_short | Internalization of Foldamer-Based DNA Mimics through a Site-Specific Antibody Conjugate to Target HER2-Positive Cancer Cells |
| title_sort | internalization of foldamer based dna mimics through a site specific antibody conjugate to target her2 positive cancer cells |
| topic | DNA mimics foldamer antibody-drug conjugate trastuzumab HER2 |
| url | https://www.mdpi.com/1424-8247/14/7/624 |
| work_keys_str_mv | AT valentinacorvaglia internalizationoffoldamerbaseddnamimicsthroughasitespecificantibodyconjugatetotargether2positivecancercells AT imeneaitmohamedamar internalizationoffoldamerbaseddnamimicsthroughasitespecificantibodyconjugatetotargether2positivecancercells AT veroniquegarambois internalizationoffoldamerbaseddnamimicsthroughasitespecificantibodyconjugatetotargether2positivecancercells AT stephanieletast internalizationoffoldamerbaseddnamimicsthroughasitespecificantibodyconjugatetotargether2positivecancercells AT aureliegarcin internalizationoffoldamerbaseddnamimicsthroughasitespecificantibodyconjugatetotargether2positivecancercells AT celinegongora internalizationoffoldamerbaseddnamimicsthroughasitespecificantibodyconjugatetotargether2positivecancercells AT maguydelrio internalizationoffoldamerbaseddnamimicsthroughasitespecificantibodyconjugatetotargether2positivecancercells AT carolinedenevaultsabourin internalizationoffoldamerbaseddnamimicsthroughasitespecificantibodyconjugatetotargether2positivecancercells AT nicolasjoubert internalizationoffoldamerbaseddnamimicsthroughasitespecificantibodyconjugatetotargether2positivecancercells AT ivanhuc internalizationoffoldamerbaseddnamimicsthroughasitespecificantibodyconjugatetotargether2positivecancercells AT philippepourquier internalizationoffoldamerbaseddnamimicsthroughasitespecificantibodyconjugatetotargether2positivecancercells |