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

Larroque-Lombard, Anne-Laure; Chatelut, Étienne; Delord, Jean‐Pierre; Imbs, D; Rochaix, Philippe; Jean‐Claude, Bertrand J.; Allal, Ben

doi:10.3390/ph14020160

Cited by 3 publications

(3 citation statements)

References 27 publications

(47 reference statements)

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“…Here, a hydrophobic protecting group, which was designed to be eliminated by intracellular enzymes, was added to confer membrane permeability to dTMP, which has been reported to be unable to permeate from outside to inside the cell. More complex and precisely controlled containment that integrates information is possible by adding conditions for elimination of protecting groups dependent on environmental signals such as light, temperature, and chemical co-factors (Bardhan and Deiters, 2019;Larroque-Lombard et al, 2021). This strategy is not limited to dTMP, but could be applied to other essential nutrients and metabolites that are difficult to uptake from outside cells.…”

Section: Discussionmentioning

confidence: 99%

A strategy for addicting transgene-free bacteria to synthetic modified metabolites

Kato

2023

Front. Microbiol.

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Biological containment is a safeguard technology to prevent uncontrolled proliferation of “useful but dangerous” microbes. Addiction to synthetic chemicals is ideal for biological containment, but this currently requires introduction of transgenes containing synthetic genetic elements for which environmental diffusion has to be prevented. Here, I designed a strategy for addicting transgene-free bacteria to synthetic modified metabolites, in which the target organism that can neither produce an essential metabolite nor use the extracellularly supplied metabolite, is rescued by a synthetic derivative that is taken up from a medium and converted into the metabolite in the cell. Because design of the synthetic modified metabolite is the key technology, our strategy differs distinctly from conventional biological containment, which mainly depends on genetic manipulation of the target microorganisms. Our strategy is particularly promising for containment of non-genetically modified organisms such as pathogens and live vaccines.

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Section: Discussionmentioning

confidence: 99%

A strategy for addicting transgene-free bacteria to synthetic modified metabolites

Kato

2023

Front. Microbiol.

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“…However, slight pH differences between a tumor stroma (pH = 7.1–6.7) [ 13 ] and the physiological condition (pH = 7.35–7.45) is impossible to be recognized by most pH-sensitive deliveries, which usually consist of pH-sensitive polymers and occur during phase transition in endocytic organelles with a lower pH value (pH ≤ 6.0), such as endosomes and lysosomes [ 9 , 10 ]. There are only a few pH-sensitive polymers with dissociation constants (p K a ) around neutral pH, such as cationic polymers with repeating ionizable tertiary amines [ 14 , 15 ] or anionic polymers with suitable sulfonamide groups [ 16 , 17 ]. Until now, the most successful pH-sensitive polymers used in targeting tumor microenvironment were cationic polymers with ionizable tertiary amine blocks, showing a hydrophobic–hydrophilic phase transition in weakly acidic microenvironments [ 18 , 19 ], which disassemble rapidly in tumor microenvironment, leading to their application in targeted tumor chemotherapy [ 20 ] and enhanced tumor fluorescence imaging [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

Tumor Microenvironment-Responsive Magnetic Nanofluid for Enhanced Tumor MRI and Tumor multi-treatments

et al. 2023

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We prepared a tumor microenvironment-responsive magnetic nanofluid (MNF) for improving tumor targeting, imaging and treatment simultaneously. For this purpose, we synthesized sulfonamide-based amphiphilic copolymers with a suitable pKa at 7.0; then, we utilized them to prepare the tumor microenvironment-responsive MNF by self-assembly of the sulfonamide-based amphiphilic copolymers and hydrophobic monodispersed Fe3O4 nanoparticles at approximately 8 nm. After a series of characterizations, the MNF showed excellent application potential due to the fact of its high stability under physiological conditions and its hypersensitivity toward tumor stroma by forming aggregations within neutral or weak acidic environments. Due to the fact of its tumor microenvironment-responsiveness, the MNF showed great potential for accumulation in tumors, which could enhance MNF-mediated magnetic resonance imaging (MRI), magnetic hyperthermia (MH) and Fenton reaction (FR) in tumor. Moreover, in vitro cell experiment did not only show high biocompatibility of tumor microenvironment-responsive MNF in physiological environment, but also exhibit high efficacy on inhibiting cell proliferation by MH-dependent chemodynamic therapy (CDT), because CDT was triggered and promoted efficiently by MH with increasing strength of alternating magnetic field. Although the current research is limited to in vitro study, these positive results still suggest the great potential of the MNF on effective targeting, diagnosis, and therapy of tumor.

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“…Thus, in recent years, strategies designed to overcome resistance mediated by compensatory signaling have involved the use of a multi-targeted approach [4,5]. Within this context, over the past decade, we developed a novel approach termed "combi-targeting" that sought to design agents designated as "combi-molecules" capable of inducing tandem blockade of two divergent biological targets (e.g., EGFR, PARP, MEK, and DNA) [6][7][8][9][10][11][12][13][14][15][16]. Further work on the concept led to the synthesis of molecules rationally designed to target two oncogenic tyrosine kinases involved in adverse signaling [17,18].…”

Section: Introductionmentioning

confidence: 99%

Quantitative Analysis of the Potency of Equimolar Two-Drug Combinations and Combi-Molecules Involving Kinase Inhibitors In Vitro: The Concept of Balanced Targeting

Rao

Thibault

Peyrard

et al. 2021

IJMS

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The median-effect principle proposed by Chou and Talalay is the most effective approach to parameterize interactions between several agents in combination. However, this method cannot be used to evaluate the effectiveness of equimolar drug combinations, which are comparative references for dual-targeting molecular design. Here, using data acquired through the development of “combi-molecules” blocking two kinases (e.g., EGFR-c-Src and EGFR-c-Met), we established potency indices for equimolar and dual-targeted inhibitors. If the fold difference (κ) between the IC50 of the two individual kinase inhibitors was >6, the IC50 of their equimolar combination resembled that of the more potent inhibitor. Hence, the “combi-targeting” of the two kinases was considered “imbalanced” and the combination ineffective. However, if κ ≤ 6, the IC50 of the combination fell below that of each individual drug and the combi-targeting was considered “balanced” and the combination effective. We also showed that combi-molecules should be compared with equimolar combinations only under balanced conditions and propose a new parameter Ω for validating their effectiveness. A multi-targeted drug is effective if Ω < 1, where Ω is defined as the IC50 of the drug divided by that of the corresponding equimolar combination. Our study provides a methodology to determine the in vitro potency of equimolar two-drug combinations as well as combi-/hybrid molecules inhibiting two different kinase targets.

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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

Cited by 3 publications

References 27 publications

A strategy for addicting transgene-free bacteria to synthetic modified metabolites

A strategy for addicting transgene-free bacteria to synthetic modified metabolites

Tumor Microenvironment-Responsive Magnetic Nanofluid for Enhanced Tumor MRI and Tumor multi-treatments

Quantitative Analysis of the Potency of Equimolar Two-Drug Combinations and Combi-Molecules Involving Kinase Inhibitors In Vitro: The Concept of Balanced Targeting

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