Design and Mechanism of Action of a New Prototype of Combi-Molecule “Programed” to Release Bioactive Species at a pH Range Akin to That of the Tumor Microenvironment
The clinical use of cytotoxic agents is plagued by systemic toxicity. We report a novel approach that seeks to design a “combi-molecule” to behave as an alkylating agent on its own and to undergo acid-catalyzed conversion to two bioactive species at a pH range akin to that of a tumor microenvironmen...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-02-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/14/2/160 |
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| author | Anne-Laure Larroque-Lombard Etienne Chatelut Jean-Pierre Delord Diane-Charlotte Imbs Philippe Rochaix Bertrand Jean-Claude Ben Allal |
| author_facet | Anne-Laure Larroque-Lombard Etienne Chatelut Jean-Pierre Delord Diane-Charlotte Imbs Philippe Rochaix Bertrand Jean-Claude Ben Allal |
| author_sort | Anne-Laure Larroque-Lombard |
| collection | DOAJ |
| description | The clinical use of cytotoxic agents is plagued by systemic toxicity. We report a novel approach that seeks to design a “combi-molecule” to behave as an alkylating agent on its own and to undergo acid-catalyzed conversion to two bioactive species at a pH range akin to that of a tumor microenvironment: an AL530 prototype was synthesized and we studied its ability to release a chlorambucil analogue (CBL-A) plus a potent mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) inhibitor (PD98059) at different pHs in buffered solutions, plasma and tumors. Its potency was compared in vitro with CBL+PD98059 (SRB assay) and in vivo in a xenograft model. Its target modulation was studied by western blotting and immunohistochemistry. AL530 released PD98059+CBL-A at mild acidic pH and in vitro was fivefold more potent than CBL and three-to-fivefold more potent than CBL+PD98059. In vivo it released high levels of PD98059 in tumors with a tumor/plasma ratio of five. It induced γ-H2AX phosphorylation and blocked pErk1,2, indirectly indicating its ability to damage DNA and modulate MEK. It induced significant tumor delay and less toxicity at unachievable doses for CBL and CBL+PD98059. We demonstrated the feasibility of a pH-labile combi-molecule capable of delivering high MEK inhibitor concentration in tumors, damaging DNA therein, and inducing tumor growth delay. |
| first_indexed | 2024-03-09T00:49:38Z |
| format | Article |
| id | doaj.art-7a380905ea964c978f154cebf9130d62 |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-09T00:49:38Z |
| publishDate | 2021-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-7a380905ea964c978f154cebf9130d622023-12-11T17:17:35ZengMDPI AGPharmaceuticals1424-82472021-02-0114216010.3390/ph14020160Design and Mechanism of Action of a New Prototype of Combi-Molecule “Programed” to Release Bioactive Species at a pH Range Akin to That of the Tumor MicroenvironmentAnne-Laure Larroque-Lombard0Etienne Chatelut1Jean-Pierre Delord2Diane-Charlotte Imbs3Philippe Rochaix4Bertrand Jean-Claude5Ben Allal6Centre de Recherches en Cancérologie de Toulouse (CRCT), Institut Claudius-Regaud–Institut Universitaire du Cancer Toulouse-Oncopole and UMR 1037 INSERM, 31052 Toulouse, FranceCentre de Recherches en Cancérologie de Toulouse (CRCT), Institut Claudius-Regaud–Institut Universitaire du Cancer Toulouse-Oncopole and UMR 1037 INSERM, 31052 Toulouse, FranceCentre de Recherches en Cancérologie de Toulouse (CRCT), Institut Claudius-Regaud–Institut Universitaire du Cancer Toulouse-Oncopole and UMR 1037 INSERM, 31052 Toulouse, FranceCentre de Recherches en Cancérologie de Toulouse (CRCT), Institut Claudius-Regaud–Institut Universitaire du Cancer Toulouse-Oncopole and UMR 1037 INSERM, 31052 Toulouse, FranceCentre de Recherches en Cancérologie de Toulouse (CRCT), Institut Claudius-Regaud–Institut Universitaire du Cancer Toulouse-Oncopole and UMR 1037 INSERM, 31052 Toulouse, FranceMcGill University Health Center (RI-MUHC), 1001 Decarie Blvd, Research Institute, Montreal, QC H4A 3J1, CanadaCentre de Recherches en Cancérologie de Toulouse (CRCT), Institut Claudius-Regaud–Institut Universitaire du Cancer Toulouse-Oncopole and UMR 1037 INSERM, 31052 Toulouse, FranceThe clinical use of cytotoxic agents is plagued by systemic toxicity. We report a novel approach that seeks to design a “combi-molecule” to behave as an alkylating agent on its own and to undergo acid-catalyzed conversion to two bioactive species at a pH range akin to that of a tumor microenvironment: an AL530 prototype was synthesized and we studied its ability to release a chlorambucil analogue (CBL-A) plus a potent mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) inhibitor (PD98059) at different pHs in buffered solutions, plasma and tumors. Its potency was compared in vitro with CBL+PD98059 (SRB assay) and in vivo in a xenograft model. Its target modulation was studied by western blotting and immunohistochemistry. AL530 released PD98059+CBL-A at mild acidic pH and in vitro was fivefold more potent than CBL and three-to-fivefold more potent than CBL+PD98059. In vivo it released high levels of PD98059 in tumors with a tumor/plasma ratio of five. It induced γ-H2AX phosphorylation and blocked pErk1,2, indirectly indicating its ability to damage DNA and modulate MEK. It induced significant tumor delay and less toxicity at unachievable doses for CBL and CBL+PD98059. We demonstrated the feasibility of a pH-labile combi-molecule capable of delivering high MEK inhibitor concentration in tumors, damaging DNA therein, and inducing tumor growth delay.https://www.mdpi.com/1424-8247/14/2/160combi-moleculesMEKsynergymicroenvironmentpharmacokinetics |
| spellingShingle | Anne-Laure Larroque-Lombard Etienne Chatelut Jean-Pierre Delord Diane-Charlotte Imbs Philippe Rochaix Bertrand Jean-Claude Ben Allal Design and Mechanism of Action of a New Prototype of Combi-Molecule “Programed” to Release Bioactive Species at a pH Range Akin to That of the Tumor Microenvironment Pharmaceuticals combi-molecules MEK synergy microenvironment pharmacokinetics |
| title | Design and Mechanism of Action of a New Prototype of Combi-Molecule “Programed” to Release Bioactive Species at a pH Range Akin to That of the Tumor Microenvironment |
| title_full | Design and Mechanism of Action of a New Prototype of Combi-Molecule “Programed” to Release Bioactive Species at a pH Range Akin to That of the Tumor Microenvironment |
| title_fullStr | Design and Mechanism of Action of a New Prototype of Combi-Molecule “Programed” to Release Bioactive Species at a pH Range Akin to That of the Tumor Microenvironment |
| title_full_unstemmed | Design and Mechanism of Action of a New Prototype of Combi-Molecule “Programed” to Release Bioactive Species at a pH Range Akin to That of the Tumor Microenvironment |
| title_short | Design and Mechanism of Action of a New Prototype of Combi-Molecule “Programed” to Release Bioactive Species at a pH Range Akin to That of the Tumor Microenvironment |
| title_sort | design and mechanism of action of a new prototype of combi molecule programed to release bioactive species at a ph range akin to that of the tumor microenvironment |
| topic | combi-molecules MEK synergy microenvironment pharmacokinetics |
| url | https://www.mdpi.com/1424-8247/14/2/160 |
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