Novel doxorubicin/folate-targeted trans-ferulic acid-loaded PLGA nanoparticles combination: In-vivo superiority over standard chemotherapeutic regimen for breast cancer treatment

Aim: Doxorubicin/Cyclophosphamide (AC) is one of the standard adjuvant anthracycline-containing regimens that is still in use for breast cancer treatment. Cancer cell resistance and AC-induced side effects make treatment suboptimal and worsen patients' quality of life. This study aimed to improve trans-ferulic acid's (TFA) efficiency via loading into folate-receptor-targeted-poly lactic-co-glycolic acid nanoparticles (FA-PLGA-TFA NPs). Also, investigating both the antitumor efficacy of Doxorubicin (Dox)/FA-PLGA-TFA NPs combination against dimethylbenz[a]anthracene (DMBA)-induced breast cancer and its safety profile. Methods: FA-PLGA-TFA NPs were optimally fabricated and characterized. Levels of Notch1, Hes1, Wnt-3a, I3-catenin, MMP-9, cyclin D1, Permeability-Glycoprotein (P-gp), ER alpha, PR, and HER2 were assessed as a measure of the antitumor efficacy of different treatment protocols. Histopathological examination of heart and bone, levels of ALT, AST, ALP, CK-MB, and WBCs count were evaluated to ensure the combination's safety profile. Key findings: Dox/FA-PLGA-TFA NPs not only inhibited Notch signaling but also suppressed Notch synergy with Wnt, estrogen, progesterone, and HER2 pathways. Interestingly, Dox/FA-PLGA-TFA NPs decreased P-gp level and preserved heart, bone, and liver health as well as WBCs count. Significance: Dox/FA-PLGA-TFA NPs reduced the side-effects of each single drug, and at the same time exerted excellent antitumor activity that surpass the AC regimen in evading cancer cell resistance and having a superior safety profile.

Automated summary

The study aimed to enhance the efficacy of trans-ferulic acid (TFA) by loading it into folate-receptor-targeted poly lactic-co-glycolic acid nanoparticles (FA-PLGA-TFA NPs) and evaluating the antitumor efficacy of Doxorubicin (Dox)/FA-PLGA-TFA NPs combination against DMBA-induced breast cancer, as well as its safety profile. The combination not only inhibited Notch signaling but also suppressed synergy with other pathways, reduced P-gp levels, and maintained organ health and white blood cell count. This approach could potentially reduce side effects and improve antitumor activity compared to the standard AC regimen.