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Assessing Compound Self-aggregation in Drug Discovery and Development

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Dlim, Marwa (2019). Assessing Compound Self-aggregation in Drug Discovery and Development Mémoire. Québec, Université du Québec, Institut National de la Recherche Scientifique, Maîtrise en sciences expérimentales de la santé, 70 p.

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Résumé

When drug-like compounds are placed in aqueous media, it is commonly understood that they can solubilize and disperse into solution as lone-tumbling molecules and/or exist as solid precipitate. However, this simplistic biphasic view is no longer valid. Instead, a triphasic model better describes compound solution behavior where compounds can also adopt an intermediate phase where compound molecules self-associate into a range of assemblies that can resemble clusters, fibers, micelles and many other forms. Although the physicochemical parameters that dictate the features of these assemblies are not yet understood, it is clear that the nature of the triphasic equilibria profoundly affects a compound’s properties, especially from the pharmaceutical perspective. We refer to these amazing assemblies as “nano-entities” and provide an introduction (Chapter 1).

This thesis aims to attract attention to these nano-entities which have, for the most part, gone undetected because they are invisible to the naked eye and detection strategies are seriously underdeveloped. We do so by first exploiting the nuclear magnetic resonance (NMR) aggregation assay that involves monitoring the solution behavior of a series of small-molecule dyes at various concentrations (see Chapter 2). This dilution-based assay demonstrates that some dyes can exist as single-molecule entities whereas others can adopt aggregates of distinct sizes. Interestingly, dyes with highly related chemical structures can adopt largely different sized aggregates - demonstrating the existence of structure-nanoentity relationships – which suggests that they can assume and/or be designed to have distinct properties. One property was evaluated where the drug Quetiapine (Seroquel) was added to the dye Congo red which resulted in the absorption of the drug into the dye nano-entity. This showed a direct drug-dye interaction, and it demonstrated that dye aggregates can have influence on drug solution behaviors. In summary, our studies demonstrate that the NMR aggregation assay can serve as a practical and valuable tool to monitor nano-entities and to better understand their associated properties (e.g. toxicity, off-target activity) and potential utility (e.g. drug encapsulation, drug delivery systems).

Chapter 3 further explores complementary strategies for detecting nano-entities. The goal was to develop, as much as possible, a combination of methods that could then be employed for correlating a compound’s properties with its physicochemical and nano-entity behavior in solution. We use several anticancer drugs (Sorafenib, Lapatinib, Gefitinib and Fulvestrant) and an antileprosy drug (Clofazimine) as model systems to better understand their physicochemical behavior and self-association properties, and to explore various techniques for probing their threestate equilibria. Their behaviors in buffers, media and cells were monitored by a combination of NMR, dynamic light scattering (DLS), transmission electron microscopy (TEM), and confocal microscopy. These drugs were found to self-associate into relatively large nano-entities having distinct types and sizes that depend on the media. Furthermore, these compounds were capable of entering cells. Noteworthy advantages and “blind spots” were observed for the various detection techniques employed. It was concluded that a combination of methods is necessary to expose these drugs’ elusive solution equilibria.

Our conclusion from the above work is that we have stumbled upon a great opportunity. Small molecules can form many types of nano-entities that depends on the media and conditions. These entities have properties – some undesired and others favorable. Our strategies can help the detection of the entities. The field is now open for exploitation purposes. For example, nanoentities could be used as drug encapsulation and drug delivery systems. This field is wide open and awaiting developments.

Type de document: Thèse Mémoire
Directeur de mémoire/thèse: Laplante, Steven
Mots-clés libres: aggregation, promiscuity
Centre: Centre INRS-Institut Armand Frappier
Date de dépôt: 21 nov. 2019 16:34
Dernière modification: 21 nov. 2019 16:34
URI: http://espace.inrs.ca/id/eprint/8517

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