Dox-HCl and miR-145 co-delivery through CD44-targeted PEGylated liposomes inhibit Breast Cancer in vitro via augmenting PI3K/AKT pathway

The aim of this study deals with integrating a CD44-targeting short peptide, A6 (KPSSPPEE) onto the PEGylated liposomes to enhance the in vitro anticancer activities of doxorubicin hydrochloride and tumor suppressor miR-145 mimics on triple-negative breast cancer. A CD44-targeting short peptide, A6 (KPSSPPEE) was integrated onto the optimized PEGylated liposomes, and its effects on cellular uptake, anti-proliferation, and anti-metastasis activities were assessed in triple-negative breast cancer, MDA-MB-231 cells. The resulting formulation (A6-PEG-lipo-Dox-miR145) demonstrated enhanced cellular uptake by CD44-expressing MDA-MB-231 cells within 2 h of incubation. In vitro study showed that A6-PEG-lipo-Dox-miR145 exerted a greater anti-proliferative activity with higher selectivity (Dox-HCl IC50 = 1.60 ± 0.07 μM; selectivity index (SI) = 1.30) against MDA-MB-231 cells when compared to MCF10A cells, which an enhanced suppression of PI3K/AKT pathway was observed, highlighting its potential as a targeted therapy for TNBC. Additionally, A6-PEG-lipo-Dox-miR145 showed anti-migration and improved anti-invasion activities on MDA-MB-231 cells, which correlated with its ability in reversing endothelial-to-mesenchymal transition (EMT) through modulating both N-cadherin and E-cadherin expression. Our findings indicate that the incorporation of A6 peptide represents a simple and straightforward strategy to improve the targetability and therapeutic effects of PEGylated liposome, warranting further investigation.