Low-Dose DOX-Polygodial Nanosystem Modulates CD47/CALR Axis for Safer Triple Negative Breast Cancer Treatment

Abstract

Triple Negative Breast Cancer (TNBC) is the most aggressive subtype of Breast Cancer (BC). Immunosurveillance significantly influences TNBC progression, drug resistance, and metastasis. Among its regulators, Cluster of Differentiation 47 (CD47) and Calreticulin (CALR) play crucial roles. This study examined the mRNA expression of CD47 and CALR in breast cancer tissues from 25 patients compared to normal tissues and investigated their role in chemoresistance at sublethal drug doses. MDA-MB-231 cells were treated with Doxorubicin (DOX), Polygodial (PG), or both, and CD47/CALR expression was analyzed at sublethal concentrations determined via MTT assay. Hyaluronic Acid (HA)-grafted chitosan nanoparticles (NP) were synthesized, loaded with DOX/PG, and characterized. Combination treatment of (DOX+PG), as well as co-loaded NPs, significantly decreased CD47 and CALR levels, reversing CD47 and CALR elevation that acts as a surrogate immunosurveillance marker and enhancing the CALR/CD47 surface expression ratio. These findings suggest a promising strategy for further examination and dose optimization in vivo studies for metastasis inhibition and as maintenance therapy.