PE38-based gene therapy of HER2-positive breast cancer stem cells via VHH-redirected polyamidoamine dendrimers

Abstract Breast cancer stem cells (BCSCs) resist conventional treatments and cause tumor recurrence. Almost 25% of breast cancers overexpress human epidermal growth factor receptor-2 (HER2). Here we developed a novel multi-targeted nanosystem to specifically eradicate HER2 + BCSCs. Plasmids containing CXCR1 promoter, PE38 toxin, 5?UTR the basic fibroblast factor-2 (bFGF 5'UTR) were constructed. Polyamidoamine (PAMAM) dendrimers functionalized with anti-HER2 VHHs used for plasmid delivery. Stem cell proportion MDA-MB-231, MDA-MB-231/HER2 MCF-10A evaluated by mammosphere formation assay. Hanging drop technique was produce spheroids. The uptake, gene expression, killing efficacy in both monolayer spheroid culture. had higher ability form compared MCF-10A. Our efficiently inhibited MDA-MB-231 cells, while it unable prevent In hanging culture, MDA-MB-231/HER generated compact well-rounded spheroids, failed cellular masses. showed much better subsequent death However, our targeted toxin therapy lower spheroids that combination surface, transcriptional, translational targeting increased stringency treatment.