Dermatan Sulfate/Chitosan Nanoparticles Loaded with an Anti-Inflammatory Peptide Increase the Response of Human Colorectal Cancer Cells to 5-Fluorouracil.

Abstract

The gold standard drug for colorectal cancer treatment, 5-Fluorouracil (5-FU), induces pharmacological tolerance in long-term management. The transcriptional factor NFκB plays a key role in 5-FU resistance. The aim of this work is to study the capability of polyelectrolytes complex nanoparticles of dermatan sulfate (DS) and chitosan, loaded with the anti-inflammatory tripeptide IRW, to sensitize colorectal cancer cells to 5-FU. Fluorescence and flow cytometry studies confirmed the recognition by the nanoformlation, of CD44 receptor, involved the initiation and progression of colorectal tumors. Dynamic light scattering and flow cytometry reinforced the importance of DS and CD44 receptor in the interaction, as the addition of DS or anti CD44 antibody blocked the binding. Moreover, the nanoformulation also interacts with 3D colon cancer cultures, namely colonospheres, enriched in cancer stem cells, subpopulation responsible for drug resistance and metastasis. To evaluate the consequences of this interaction, the subcellular distribution of the transcriptional factor NFκB, was determined by immunofluorescence analysis. Internalization and the intracellular release of IRW inhibited nuclear translocation of NFκB and increased cellular sensitivity to 5-FU. Altogether, the nanoformulation could provide a selective delivery platform for IRW distribution to colorectal tumors, being an innovative strategy towards overcoming 5-FU resistance in colorectal cancer therapy. This article is protected by copyright. All rights reserved.