The nucleolin antagonist N6L and paclitaxel combination treatment could be a new promising therapeutic strategy for pancreatic ductal adenocarcinoma therapy

Abstract

Pancreatic cancer (PCa) is one of the most devastating cancers with few clinical signs and no truly effective therapy. In recent years, our team has demonstrated that nucleolin antagonists such as N6L could be a therapeutic alternative for this disease.

In order to study a possible clinic development of N6L (multivalent pseudopeptide), we undertook to study the effect of combination of N6L with chemotherapies classically used for PCa on the survival of pancreatic cancer cells. Thus, the combined effect of N6L with either gemcitabine, FOLFOX and paclitaxel (PTX) on the survival of PANC-1, Mia-PaCa-2 and BxPC3 was studied and shown additive effect. In addition, analysis of the data by Combenefit software indicates that there are synergistic effects between N6L and the 3 chemotherapy molecules tested with more sensitive effects with the N6L-PTX combination. This result was confirmed by associating N6L and paclitaxel on porous calcium carbonate particles loaded with cyclodextrin (CD) encapsulating PTX and carrying N6L at their surface. Porous calcium carbonate particles present highly benefits for biological purposes because of their large surface area and their high stability in neutral media. As for CD, it presents the advantage of owing hydrophilic exterior and a less polar cavity in the center. We have then combined the advantageous features of both porous and negatively charged surfaces of calcium carbonate (CaCO₃) particles and host molecules CD for developing carrier enabling all at once the loading of PTX (hydrophobic drug) and N6L (cationic drug). This association generates water-soluble particles capable of targeting via N6L and delivering paclitaxel to tumor cells.