Lipodisks for dual delivery of pirarubicin and melittin: physicochemical properties and in vitro evaluation

Nanocarrier-based combination therapy can enhance anticancer efficacy by reducing systemic toxicity, overcoming drug resistance, and enabling synergistic interactions, but requires nanocarriers capable of efficiently loading and retaining structurally diverse therapeutic agents. While lipid-based nanoparticles such as liposomes are widely employed due to their intrinsic biocompatibility, they are often unsuitable for membranolytic compounds like the peptide melittin. Polyethylene glycol (PEG)-stabilized lipodisks, discoidal lipid assemblies with well-defined high curvature rim domains, have recently been shown to accommodate therapeutically relevant quantities of melittin together with doxorubicin. Here, we evaluate PEG-stabilized lipodisks as co-delivery vehicles for melittin and tetrahydropyranyl adriamycin (THP, pirarubicin), a more potent and less hydrophilic anthracycline. We examine how lipid composition affects THP loading and retention, identify factors governing melittin binding, and evaluate cytotoxicity of lipodisk delivering each drug individually or in combination. Although the lipodisks exhibit somewhat lower loading capacity for THP compared to doxorubicin, the retention of the former is markedly superior. Importantly, the potential for synergistic effects is clearly greater when THP and melittin are co-delivered via dual-loaded lipodisks compared to administered as free drug mixtures (average CI: 0.83 ± 0.17 vs. 1.11 ± 0.21). These findings highlight PEG-stabilized lipodisks as a promising platform for anthracycline–melittin combination therapy.