Therapeutic evaluation of paclitaxel co-loaded PLGA nanoparticles with imatinib, protamine-imatinib, and gefitinib: comparative in vitro studies in MDA-MB-231 breast cancer cells and in vivo investigations in rats.

The current study investigates the therapeutic potential of paclitaxel (PX) co-loaded with imatinib (IMT), IMT with protamine (PT), and gefitinib (GF) nanoparticle (NP) formulations against triple-negative breast cancer (TNBC) to overcome drug resistance. Building upon our previous work where the SR-F-I (PX-IMT-PLGA NPs), SR-F-I (coated) as PX-IMT-PT-PLGA-NPs, and SR-F-II (PX-GF-PLGA NPs) formulations were optimized and evaluated in both MCF-7 and MCF-7/ADR cells, we extended our investigation to MDA-MB-231 TNBC cells and in vivo animal model. Comparative in vitro cytotoxicity studies demonstrated that SR-F formulations, especially SR-F-I (coated) and SR-F-II, significantly enhanced drug delivery and cell death compared to free PX and combination conventional drug solutions. Confocal imaging confirmed improved NP internalization, correlating with increased cytotoxic efficacy. In vivo, SR-F formulations exhibited reduced tumor growth volumes, lower prostaglandin-2 (PGs-2) levels, and diminished tumor markers (tumor necrosis factor-alpha; TNF-α and breast cancer Antigen 15-3; CA 15-3), indicating reduced inflammation and tumor burden. Histopathological evaluations of SR-F formulations revealed improved tissue repair and organized fibrosis in mammary tissue. Our findings thus highlight the superior potential of co-loaded polymeric NPs in targeted cancer therapy, with an enhanced safety profile, therapeutic outcomes, and modulation of systemic inflammation. The co-loaded formulation of PX with IMT and GF presents a promising strategy for advancing breast cancer treatment.