Controlling release from the lipidic cubic phase by selective alkylation

The lipidic cubic phase can be viewed as a molecular sponge consisting of interpenetrating nanochannels filled with water and coated by lipid bilayers. It has been used as a delivery matrix for low-molecular-weight drugs. For those that are water-soluble, release is fast and unregulated. This study seeks to exploit the lipid bilayer compartment as a location within the cubic phase in which to 'hydrophobically' anchor the water-soluble drug. This was accomplished by controlling partitioning into, and thus release from, the aqueous compartment of the cubic phase. Tryptophan was used as a surrogate water-soluble drug and alkylation was implemented to regulate release. By adjusting alkyl chain length, exquisite control was realized. Without alkylation, 20% of the tryptophan was released under standard conditions (infinite sink with a 30-mg cubic phase source at pH 7 and 20 °C) over a period of 30 min (t20). In the case of derivatives with alkyl chains two and eight carbon atoms long, t20 values of 3 and 13 days, respectively, were observed. Eliminating the charge on tryptophan completely by alkylation produced a derivative that became irreversibly lodged in the lipid bilayer. The release behavior of the short-chain derivatives was mathematically modeled and parameters describing transport have been obtained. Cubic phase partition coefficients for tryptophan and its derivatives were measured to facilitate modeling. The implications of these findings with regard to the cubic phase and related delivery systems, and to vaccine efficacy are discussed.