Vahid Forooqi Motlaq: Self-assembly in aqueous mixtures of amphiphilic drugs and phospholipids: When drugs behave like surfactants: Structural and compositional effects on self-organization in amphiphilic drug–phospholipid mixtures

Abstract

Although the term surfactant was coined in the mid-20th century, substances with surfac-tant-like properties have been known to humans for millennia. Comprising two distinct parts, referred to as the tail and the head, surfactants are well known for their ability to lower the surface tension between two phases, such as liquid and air or liquid and liquid. Several natural and synthetic materials exhibit amphiphilic properties similar to conventional surfactants, in-cluding phospholipids, bile salts, certain proteins, and pharmaceuticals. Like ordinary surfac-tants, amphiphilic drugs can self-associate into larger aggregates at higher concentrations. They can be found in several drug categories, for instance analgesics, tranquilizers, antidepressants, and antihistamines. As a result, these compounds can be referred to as drug surfactants. The self-assembly of drug surfactants is influenced by additional molecules such as proteins, lipids, and amphiphilic drugs. Drug surfactants can integrate into biological aggregates, such as mi-celles, bilayers, and liposomes, and can substantially impact their structures, eventually influ-encing their pharmacological activity and toxicity. The overall aim of this thesis was to enhance the understanding of the interactions between amphiphilic drugs and phospholipids, with spe-cial emphasis on the self-assembly of amphiphilic drug-phospholipid binary systems by study-ing their self-associated aggregates. The main focus was on two tricyclic antidepressants (ami-triptyline and doxepin) and a group of selected phosphatidylcholine (PC) phospholipids (DOPC, DEPC, DMPC, and DPPC).Results presented in this thesis demonstrate the enhanced ability of drug surfactants to sol-ubilize PC phospholipids, beyond the capacity of conventional surfactants through the for-mation of mixed micelles. With increasing lipid content, all binary drug-lipid systems reached a micelle-to-bilayer transition point, beyond which bilayer structures, i.e. vesicles and disks were observed in the samples. Within the bilayer region, spontaneous formation of vesicles was observed in different phospholipid-drug binary series. For some samples, vesicles were the pre-dominant self-assembled structure. Vesicle size showed a downward trend as the total concen-tration decreased, in contrast to the behavior of micellar aggregates. Notably, the smallest ves-icles measured less than 10 nm in radius; we have chosen to denote them ultrasmall vesicles. The observed ultrasmall vesicles remained intact for several months, indicating their thermo-dynamic stability and their promise for potential nano-carrier drug delivery and other nanotech-nology applications.In addition, the effects of phospholipid tail (acyl chain) chemical structure, specifically the degree of unsaturation, on the self-assembled aggregates were investigated. Moreover, the in-teraction between a selected drug surfactant (amitriptyline) and supported DOPC bilayer was also studied. In addition, since the properties and behavior of bile salts resemble those of am-phiphilic drugs, they were also investigated in this work.