الفهرس 
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Abstract
Aim : Doxorubicin/Cyclophophamide (AC) is one of the standard adjuvant anthracycline-containing regimens that 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 the efficiency of piperine (PIP) and trans-ferulic acid (TFA) via loading into folate-receptor-targeted-poly lactic-co-glycolic acid nanoparticles (FA-PLGA-PIP NPs and FA-PLGA-TFA NPs, respectively). Also, investigating both the antitumor efficacy of Doxorubicin (Dox)/FA-PLGA-PIP NPs and Dox/FA-PLGA-TFA NPs combinations against dimethylbenz[a]anthracene (DMBA)-induced breast cancer and its safety profile. Methods: FA-PLGA-PIP NPs and FA-PLGA-TFA NPs were optimally fabricated and characterized. Levels of Notch1, Hes1, Wnt-3a, β-catenin, MMP-9, cyclin D1, Permeability-Glycoprotein (P-gp), ERα, 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 combination’s safety profile. Key findings: Dox/FA-PLGA-PIP NPs and Dox/FA-PLGA-TFA NPs not only inhibited Notch signaling, but also suppressed Notch synergy with Wnt, estrogen, progesterone and HER2 pathways. Interestingly, these combinations decreased P-gp level and preserved heart, bone and liver health as well as WBCs count. Significance: Dox/FA-PLGA-PIP NPs and 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 superior safety profile.