Resumen de Self-assembled pseudopeptidic systems for the encapsulation and control release of active compounds
Ahmed Hajjaj Lotfallah Mohamed Ahmed
The current thesis entitled New pseudopeptidic compounds with potential biomedical applications deals with the synthesis of a new second generation of gemini amphiphilic pseudopeptides (GAPs), as well as the study of their self-assembly properties. In addition, the GAP 5a (A4NVal_a10obenz) was investigated as delivering vehicle for organic molecules in aqueous environment, with potential biomedical applications. Such dissertation has been divided into five chapters, being their corresponding contents summarized in the next paragraphs.
The first chapter involves a general introduction where important aspects of supramolecular chemistry, bottom-up approach, self-assembly process, biomimetic chemistry and peptidomimetics as new medicines are reviewed. These are presented together with definitions, examples and selected references described in the literature. Following the introduction, the general objectives of the whole thesis are also presented.
The second chapter describes the synthesis of the new gemini amphiphilic pseudopeptides (GAPs) as second generation, following the general procedure that was developed in our group. Moreover, these new GAPs were fully characterized by techniques commonly used in organic chemistry such as NMR, IR, mass spectrometry, elemental analysis, melting point and polarimetry.
The third chapter presents the self-assembly properties of the second generation gemini amphiphilic pseudopeptides (GAPs). In the solid state, the prepared new GAPs were capable of forming fibers and vesicles from aqueous methanol and acidic aqueous methanol respectively, particularly for the 5a Val derivative, as revealed by different (SEM, TEM and AFM) microscopy techniques. The critical aggregation concentrations (CAC) of the second generation GAPs were measured by pyrene 1:3 ratio fluorescence method in the liquid state. Accordingly, a convenient system for this measurement has been fulfilled using biocompatible conditions (i.e. citric / citrate buffer). Consequently, such second generation of GAPs could act as stimuli responsive materials. The conformational properties of the GAPs have been studied using different spectroscopic techniques (NMR, CD, UV-vis spectroscopy) in the liquid pre- aggregated state. The transition from the solution state to the solid aggregate has been monitored by ATR-IR spectroscopy. Furthermore, the thermal behavior of these GAPs was investigated by differential scanning calorimetry and optical normal/polarized light microscopy. These thorough studies certainly revealed the main non-covalent interactions responsible for the hierarchic self-assembly into different microstructures and underscored the importance of the different structural parameters, such as the central aliphatic spacer and, specially, the nature of the amino acid side chain.
In the fourth chapter, the ability of GAP 5a (A4NVal_a10obenz) to form oil-in-water emulsions was tested. These oil-in-water emulsions showed high stability to mechanical, thermal stress as well as to acidic media, although it disassembled in strongly basic medium or upon the action of a peptidase enzyme. In addition, the complementary studies on the encapsulation of propranolol and Na fluorescein probe as models of organic drugs were carried out. Hence, important potential biomedical applications as drug / active substance carriers can be foreseen for them.
The dissertation presentation finishes with the fifth chapter, thesis conclusions, where the most relevant conclusions extracted from the previous chapters are compiled.
