The design of efficient liposomal systems for drug delivery is of considerable biomedical interest. In this context, vesicles prepared from cationic/anionic surfactants may offer several advantages, mainly due to their spontaneity in formation and long-term stability. There is also an impending need to produce less toxic, more biocompatible amphiphiles, while maintaining the desirable aggregation properties. In this work, we present data for acute toxicity to Daphnia magna (IC(50)), and potential ocular irritation (HC(50)) for some newly prepared ionic surfactants with dodecyl chains, derived from the amino acids tyrosine (Tyr), serine (Ser), hydroxyproline (Hyp) and lysine (Lys). The micellization behavior of the compounds, evaluated from surface tension measurements, is presented and compared to more conventional ionic amphiphiles. Two types of spontaneouly formed catanionic vesicles, composed either by a dodecyltrimethylammonium bromide (DTAB)/Lys-derivative and or Ser-/Lys-derivative mixture, have also been tested for their ecotoxicity and hemolytic potential. All the micelle-forming surfactants as well as the vesicle-containing mixtures are found to have lower ecotoxicity than the reference surfactant DTAB. Moreover, the results from hemolysis and hemoglobin denaturation tests show that the Tyr- and Lys-derivatives are moderately irritant, whereas the Hyp- and Ser- ones are just slightly irritant. Even more significantly, the vesicle-containing mixtures exhibit lower hemolytic activity than the neat surfactants, a positive result for their potential use in liposomal formulations.

The use of amino acids for the synthesis of novel surfactants with vesicle-forming properties potentially enhances the biocompatibility levels needed for a viable alternative to conventional lipid vesicles. In this work, the formation and characterization of catanionic vesicles by newly synthesized lysine- and serine-derived surfactants have been investigated by means of phase behavior mapping and PFG-NMR diffusometry and cryo-TEM methods. The lysine-derived surfactants are double-chained anionic molecules bearing a pseudogemini configuration, whereas the serine-derived amphiphile is cationic and single-chained. Vesicles form in the cationic-rich side for narrow mixing ratios of the two amphiphiles. Two pairs of systems were studied: one symmetric with equal chain lengths, 2C₁₂/C₁₂, and the other highly asymmetric with 2C₈/C₁₆ chains, where the serine-based surfactant has the longest chain. Different mechanisms of the vesicle-to-micelle transition were found, depending on symmetry: the 2C₁₂/C₁₂ system entails limited micellar growth and intermediate phase separation, whereas the 2C₈/C₁₆ system shows a continuous transition involving large wormlike micelles. The results are interpreted on the basis of currently available models for the micelle−vesicle transitions and the stabilization of catanionic vesicles (energy of curvature vs mixing entropy).

Transdermal drug delivery (TDD) presents many advantages compared to other conventional routes of drug administration, yet its full potential has not been achieved. The administration of drugs through the skin is hampered by the natural barrier properties of the skin, which results in poor permeation of most drugs. Several methods have been developed to overcome this limitation. One of the approaches to increase drug permeation and thus to enable TDD for a wider range of drugs consists in the use of chemical permeation enhancers (CPEs), compounds that interact with skin to ultimately increase drug flux. Amino acid derivatives show great potential as permeation enhancers, as they exhibit high biodegradability and low toxicity. Here we present an overview of amino acid derivatives investigated so far as CPEs for the delivery of hydrophilic and lipophilic drugs across the skin, focusing on the structural features which promote their enhancement capacity.

Self-assembled vesicles composed of amino acid-based cationic/anionic surfactant mixtures show promise as novel effective drug nanocarriers. Here, we report the in vitro performance of vesicles based on cationic (16Ser) and anionic (8–8Ser) serine-based surfactants using a cancer cell model for the delivery of the anticancer drug doxorubicin (DOX). This catanionic mixture yields both negatively (0.20 in the cationic surfactant molar fraction, x_16Ser) and positively (x_16Ser = 0.58) charged vesicles, hence providing a surface charge tunable system. Low toxicity is confirmed for concentration ranges below 32 μM in both formulations. DOX is successfully encapsulated in the vesicles, resulting in a surface charge switch to negative for the (0.58) system, making both (0.20) and (0.58) DOX-loaded vesicles highly interesting for systemic administration. High uptake by cells was demonstrated using flow cytometry and confocal microscopy. Drug accumulation results in an increase of cell uptake up to 250% and 200% for the (0.20) and (0.58) vesicles, respectively, compared to free DOX and with localizations near the nuclear regions in the cells. The in vitro cytotoxicity studies show that DOX-loaded vesicles induce cell death, confirming the therapeutic potential of the formulations. Furthermore, the efficient accumulation of the drug inside the cell compartments harbors the potential for optimization strategies including phased delivery for prolonged treatment periods or even on-demand release.