EGFR-targeted micelles-in-lipopolymersome nanocarriers for overcoming drug resistance in triple-negative breast cancer

Triple-negative breast cancer (TNBC) remains a therapeutic challenge due to its aggressive nature, limited treatment options, and propensity for developing multidrug resistance (MDR). To overcome these limitations, a novel micelles-in-lipopolymersome nanocarrier system is developed herein for targeted drug delivery. Specifically, an epidermal growth factor receptor (EGFR)-targeted EGF peptide is conjugated to 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000] (DSPE-PEG-NH₂) and subsequently incorporated into micelles, which significantly reduces the critical micelle concentration (CMC) and enhances the structural stability. The paclitaxel (PTX)-loaded micelles (designated Micelle@PTX) exhibit pronounced pH-sensitive behavior, being less stable under acidic conditions, thereby facilitating rapid drug release in a tumor-like microenvironment. To further improve its stability and control the drug release, Micelle@PTX is encapsulated within lipopolymersomes to obtain Lipo-Micelle@PTX particles with sizes ranging from 120 to 150 nm. Notably, the as-fabricated system effectively co-delivers hydrophobic PTX and hydrophilic irinotecan (CPT-11), thereby illustrating its versatility for combination chemotherapy. In vitro release experiments demonstrate that both PTX and CPT-11 are released more rapidly at pH 6.5 than at pH 7.4. Cellular uptake studies, supported by confocal microscopy and FACS analysis, reveal enhanced internalization of the EGFR-targeted nanocarriers in drug-resistant BT-20 LUC/MDR cells, thus resulting in improved cytotoxicity compared to free PTX. Preliminary in vivo studies further demonstrate that Lipo-Micelle@PTX significantly inhibits tumor growth compared to PTX alone, without inducing detectable systemic or organ toxicity. This study presents a promising platform for overcoming drug resistance in TNBC, with potential implications for targeted cancer therapy and improved clinical outcomes.