Abstract by Luna Gade Sørensen

Stimuli-responsive drug delivery systems can release their drug cargo with spatiotemporal control, offering several advantages such as enhanced therapeutic efficacy and reduction of adverse drug effects. For patients suffering from chronic inflammatory skin diseases such as psoriasis, formulations with stimuli-responsive properties potentially provide an advantageous long-term treatment strategy, where a triggered drug release in response to stimuli induced by the initial stages of a disease should alleviate symptoms before they evolve. Upregulation of phospholipase A2 (PLA2) in the skin of psoriatic patients motivates the development of a PLA2-responsive drug delivery system, which has already proven useful in the context of other diseases. In this regard, dispersed non-lamellar liquid crystalline particles of the reversed bicontinuous cubic phase (cubosomes) are interesting platforms since the incorporation of amphiphiles such as phospholipids can alter the mesophase morphology which dictates drug delivery performance. Therefore, the aim of this project was to develop phospholipid-containing cubosomes, explore their susceptibility to PLA2 digestion and whether this feature can be utilized to trigger a drug release.

Incubation of cubosomes containing 0-10% DMPC, DPPC, POPC, or DOPC with PLA2 generally induced decrease in zeta-potential, swelling of the water channel network, and Pn3m-to-Im3m phase transition caused by the formation of PLA2-formed reaction products, i.e. lysophospholipids and deprotonated free fatty acids, driving the negative membrane curvature towards more neutral values. The effect could be tuned by increasing the phospholipid content, or by using phospholipids with shorter alkyl chains or higher degrees of unsaturation. Increasing amounts of the PLA2 cofactor Ca2+ further enhanced the structural change, however excessive levels of the cation counteracted the swelling due to charge screening of the free fatty acids.

The release of the skin-relevant small molecule model drugs tofacitinib citrate, betamethasone, ibuprofen, and tazarotene from phospholipid-containing cubosomes was not affected by the addition of PLA2. For drugs able to partition out in the aqueous phase the absent PLA2-triggered release was explained by the burst-release behavior of cubosomes, diminishing the impact of the PLA2-induced structural change. For more lipophilic drugs that stayed within the lipid bilayer membranes, re-design of the lipid composition was proposed as a viable strategy to obtain PLA2-triggered drug release.

Using dextran polymers and gold nanoparticles as larger hydrophilic model compounds resulted in better entrapment due to confinement by the water channel network, however the PLA2-induced structural effects did not result in enhanced release. In order to explain these results, further experiments clarifying the penetration depth of the enzyme along with optimization of the experimental setup for the release studies are needed.

In conclusion, phospholipid-containing cubosomes hold potential in the field of PLA2-responsive drug delivery. Better understandings of the drug-cubosome and cubosome-PLA2 interactions would be beneficial for further development and improvement of the system to obtain PLA2-triggered drug release.