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 IC50 as opposed to free DOX (2.5 {micro}M vs 25.7{micro}Mrespectively, 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. Graphical abstact O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/631287v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@283f0forg.highwire.dtl.DTLVardef@43fa12org.highwire.dtl.DTLVardef@d6d5baorg.highwire.dtl.DTLVardef@69e65d_HPS_FORMAT_FIGEXP M_FIG C_FIG Figure Graphical abstract of the study. Fron left to right, development of nanoparticles formulation a followed by characterization and efficacy of the nanoparticle formulation in in vitro and in vivo to reduce drug resistance and target triple negative breast cancer (TNBC). PLGA: polylactic-co-glycolic acid, PEG: polyethylene glycol, A6: A6 peptide, DOX: Doxorubicin, AM21: antisense-microRNA -21 HighlightsO_LIThe nanoparticle of A6 conjugated PLGA-PEG co-loaded Doxorubicin with anti-miRNA21 (NPA6.DOX.AM21) was successfully fabricated with the size of 99.8 - 103.5 nm diameter and PDI 0.2 with high drugs encapsulation efficiency. C_LIO_LINPA6.DOX.AM21 increased cell death, reduced drug resistance in MDA MB-231 resistant cells, and reduced IC50 of doxorubicin dose. C_LIO_LINPA6.DOX.AM21 targeted and reduced TNBC tumour size, with high doxorubicin distribution in tumor and less accumulation in off-target organs, in comparison to the control in mice model. C_LI