Design and Synthesis of Peptide-Tagged Cubosome Nanocarriers for the Targeted Delivery of Paclitaxel in EGFR Overexpressing Breast Cancer

Targeted delivery of chemotherapeutic agents can reduce systemic toxicity and enhance therapeutic outcomes by increasing the level of drug accumulation at tumor sites. In this study, we developed lipid-based cubosomal nanocarriers with an optimal size of 157 ± 20 nm for effective tumor penetration. This work represents the first demonstration of actively targeting cubosomes to epidermal growth factor receptors (EGFR) using a short peptide ligand. The peptide-functionalized cubosomes exhibited selective uptake of up to 75% in EGFR-overexpressing MDA-MB-468 breast cancer cells while showing minimal uptake (9%) in EGFR-negative HEK-293 cells. Paclitaxel-loaded targeted cubosomes significantly reduced MDA-MB-468 cell viability (47% survival at 60 μg/mL after 24 h) with negligible cytotoxicity in HEK-293 cells (87% survival). In 3D spheroid models, the survivability further decreased to 13% in MDA-MB-468 spheroids after 48 h, whereas HEK-293 spheroids remained largely unaffected. In vivo, targeted treatment suppressed tumor progression, yielding a mean tumor volume of 330 mm³, compared to 675 mm³ and 770 mm³ in untargeted and control groups, respectively, without observable liver or kidney toxicity. These results highlight the therapeutic potential of peptide-tagged cubosomes for the selective treatment of EGFR-expressing cancers.