Fluorescent self-assembled micellar nanometers for the evaluation of lipophilicity and acidity of fatty acids, penicillins and non-steroidal anti-inflammatory drugs

Evaluation and parametrization of lipophilicity is an important step in profiling drug-like properties of new molecules for their pharmaceutical use, in particular as regards oral absorption and brain uptake. We have studied an approach in which micelles behave as nanocontainers promoting the self-assembly of multicomponent molecular devices. These devices exist exclusively inside the nanosized and poorly hydrated micellar core, and are capable of measuring molecular lipophilicity by means of a fluorescent signal. The variation of fluorescence intensity is proportional to the capability of a given molecule to penetrate the palisade layer of a micelle and to reach the hydrophobic core, as once it is inside the nanocontainer it competes with a receptor-fluorescent substrate assembly. In turn, this molecular ability is directly related to its lipophilicity. Our micellar nanometers represent an advancement with respect to traditional lipophilicity evaluation methods, as micelles can mimic the natural bi-layer of cellular membranes. Moreover, being systems working in water, they allow to directly compare the effective lipophilicity of a chosen series of molecules under real-world, in vivo conditions, e.g. as regards working pH, concentration of electrolites, solution background, temperature. The effective values inside a membrane-like environment of chemical-physical parameters (e.g. the pKa of the acid fragment of a large molecule) can also be evaluated in parallel. Changing the contained fluorescent assembly or the micellar nanocontainer, the lipophilicity of different series of molecules can be parametrized, as we have demonstrated by stepping from linear fatty acids[1] and bicarboxylic acids, to penicillins and non-steroidal anti-inflammatory drugs