Development and in vitro evaluation of lipodisks optimized for co-delivery of chemotherapeutic drugs and membranolytic anticancer peptides

Polyethylene glycol (PEG)-stabilized lipodisks constitute a novel and promising class of drug nanocarriers. Their non-spherical shape, small size and deformable morphology confer advantageous features in terms of blood circulation time, biodistribution, tumour penetration and immunological behaviour. In this study, we explore the potential and conditions for using lipodisks for the co-delivery of the membranolytic anticancer peptide melittin and the chemotherapeutic agents doxorubicin (DOX) or SN-38. To this end we prepare lipodisks loaded with DOX or SN-38 alone, as well as lipodisks dually loaded with DOX or SN-38 and melittin. We investigate how variations in the lipodisk lipid composition affects the disk's drug loading capacity, and identify factors that have an important influence on the retention of the anticancer agents in the disks. Additionally, we conduct cell studies to assess and compare the in vitro cytotoxic effects of the mono and dually drug-loaded lipodisks. These studies include experiments designed to explore possible synergistic effects obtained by combining DOX or SN-38 with melittin in the same carrier. Our results indicate that clear synergistic effects can be obtained by co-delivery of SN-38 and melittin (combination index (CI) ≤ 0.52), while the benefits achieved by combining doxorubicin and melittin in a common lipodisk carrier are more modest (CI ≤ 0.95). In conclusion, our study highlights the potential of PEG-stabilized lipodisks as effective nanocarriers for the co-delivery of membranolytic peptides and chemotherapeutic agents. The overall findings underscore the versatility and promise of lipodisks in drug delivery applications.