Paclitaxel-loaded nanostructured lipid carriers surface-functionalized with N6L for pancreatic cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most aggressive and lethal malignancies, with limited therapeutic options. Despite advances in chemotherapy, such as FOLFIRINOX and Abraxane® (nab-paclitaxel) combined with gemcitabine, these treatments show limited efficacy due to systemic toxicity, poor tumor specificity, and drug resistance. Nanomedicine offers a promising strategy to improve drug delivery, reduce off-target effects, and enhance therapeutic efficacy. In this study, we developed and physicochemically characterized paclitaxel (PTX)-loaded nanostructured lipid carriers (NLC) surface-functionalized with the nucleolin-targeting pseudopeptide N6L, prepared by the solvent displacement method and coated via electrostatic adsorption. Diluted PTX-loaded NLC displayed a mean hydrodynamic diameter of 165 ± 5 nm, a polydispersity index of 0.14 ± 0.09, and a zeta potential of -28 ± 1 mV. Following N6L adsorption, the zeta potential shifted to + 40 mV, confirming successful surface functionalization, while drug loading corresponded to 1.48 µg PTX per mg of lyophilized formulation (0.148% w/w). Freeze-drying with 25% (w/v) sorbitol as a cryoprotectant preserved particle size and colloidal integrity upon redispersion, supporting suitability for long-term storage. Cytotoxicity assays on PANC-1 pancreatic cancer cells using the MTT assay revealed that N6L-functionalized PTX-loaded NLC reduced cell viability to 23% at the highest concentration tested, corresponding to an approximately 20% increase in cytotoxicity compared with blank NLC. These preliminary results demonstrate the feasibility of engineering N6L-functionalized PTX-loaded NLC with suitable physicochemical properties, colloidal stability, and antitumor activity, supporting their potential as a nanocarrier platform for pancreatic cancer therapy.