ArticlePharmaceuticals (Basel, Switzerland)2021
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.
Article in Pharmaceuticals (Basel, Switzerland), 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
What it found
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Who cites it
4 citing papers in PubMed, 5 citations in OpenAlex.
- Dual-Targeting CSC Therapy: Acid-Responsive Cisplatin/CaCOPharmaceuticals (Basel, Switzerland) · 2025Article
- Tumor Microenvironment-Responsive Magnetic Nanofluid for Enhanced Tumor MRI and Tumor multi-treatments.Pharmaceuticals (Basel, Switzerland) · 2023Article
- A strategy for addicting transgene-free bacteria to synthetic modified metabolites.Frontiers in microbiology · 2023Article
- Quantitative Analysis of the Potency of Equimolar Two-Drug Combinations and Combi-Molecules Involving Kinase Inhibitors In Vitro: The Concept of Balanced Targeting.International journal of molecular sciences · 2021Article
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Authors and funding
7 authors at 4 institutions in 2 countries.
Funding
Abstract
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.
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