Targeting and combating drug resistance in triple-negative breast cancer using nano polymer: Efficacy of A6 peptide-PLGA-PEG nanoparticle loaded with doxorubicin and anti-miR-21 in in vitro and vivo model

Triple-negative breast cancer (TNBC) poses a significant challenge in treatment due to the emergence of drug resistance to standard chemotherapeutics, along with associated risks to non-targeted tissues. This study is dedicated to developing a nanoparticle drug delivery system utilizing PLGA-PEG nanoparticles (NP) with the integration of A6 peptide (NPA6) as a specific targeting ligand for TNBC. Encapsulating Doxorubicin (DOX) and antisense-miR-21 (AM21), these nanoparticles are designed to counter drug resistance in vitro and in vivo. Characterized by an average size of 103.5 (±8.1) nm and remarkable DOX encapsulation efficiency, these nanoparticles have been successfully engineered. Results demonstrate that NPA6.DOX.AM21 effectively mitigates drug resistance, displaying a significantly decreased doxorubicin IC ₅₀ as opposed to free DOX (2.5 µM vs 25.7µMrespectively, p<0.01). In mice models, the A6 peptide-incorporated formulation (NPA6.DOX, NPA6.DOX.AM21) exhibits substantial tumour size reduction and increased doxorubicin concentration within tumours, all while minimizing non-specific doxorubicin exposure compared to non-A6 formulations (NPDOX, FREE DOX) treatments. This innovative PLGA-PEG-A6 peptide complex loaded with DOX and AM21 showcases superior efficacy in surmounting cell resistance in breast cancer cell line, targeting tumour progression, and decreasing drug distribution in non-targeted organs in mice. These results hold promise for enhanced combat against drug resistance and precise chemotherapy, hence potentially improving patient outcomes and survival rates.