Peganum harmala Alkaloids and Tannic Acid Encapsulated in PAMAM Dendrimers: Improved Anticancer Activities as Compared to Doxorubicin AITranslate

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DOI：https://doi.org/10.1021/acsapm.2c01093

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pH-responsive dual-loaded nanoplatforms based on polyamidoamine dendrimer with a hydroxyl-terminated surface (PAMAM–OH), generations 3, 4, and 5 (G3, G4, and G5, respectively), were loaded with Peganum harmala alkaloid extracts (H) and tannic acid (TA) and tested against breast cancer cells. G3 dendrimers encapsulating the drugs showed the smallest sizes, PDI, and highest ζ-potential and entrapment efficiencies compared to those of G4 and G5. G3 dendrimers loaded with either doxorubicin (DOX), H, or TA or dual-loaded with H+TA were prepared. The average diameters of the designed DOX@G3, H@G3, TA@G3, and H+TA@G3 NPs were 78 ± 5.1, 122 ± 3.7, 141 ± 2.8, and 192 ± 1.9 nm, respectively. All of the prepared NPs exhibited high positive surface charges and high entrapment efficiencies. Release studies showed the ability of the dendrimers to release their cargo selectively in the cancerous cells’ extracellular pH (pH 5.5) via a pH-triggered mechanism while maintaining an outstanding stability at physiological conditions (pH 7.4). Furthermore, H@G3, TA@G3, and H+TA@G3 NPs exhibited remarkable cytotoxic activities against breast adenocarcinoma (MCF-7) cells with IC50 values of 2.6 ± 0.08, 4.5 ± 0.9, and 1.7 ± 0.6 μg/mL, respectively, as compared to free H, free TA, free DOX, and DOX@G3 (IC50 values of 5.8 ± 0.8, 7.2 ± 1, 6.75 ± 0.7, and 4.7 ± 0.8 μg/mL). The formulated H@G3, TA@G3, and DOX@G3 exhibited 11.8, 9.3, and 5.3% increases in late apoptosis in MCF-7 cells relative to their respective free forms, while H+TA@G3 exhibited the highest percentage of late apoptosis in MCF-7 cells. In conclusion, G3 PAMAM–OH dendrimers dually loaded with Peganum harmala alkaloids and tannic acid hold the potential for effective treatment of breast cancer.