We present here the development of multifunctional doxorubicin (DOX)-conjugated\npoly(amidoamine) (PAMAM) dendrimers as a unique platform for pH-responsive drug release\nand targeted chemotherapy of cancer cells. In this work, we covalently conjugated DOX onto the\nperiphery of partially acetylated and folic acid (FA)-modified generation 5 (G5) PAMAM dendrimers\nthrough a pH-sensitive cis-aconityl linkage to form the G5.NHAc-FA-DOX conjugates. The formed\ndendrimer conjugates were well characterized using different methods. We show that DOX release\nfrom the G5.NHAc-FA-DOX conjugates follows an acid-triggered manner with a higher release rate\nunder an acidic pH condition (pH = 5 or 6, close to the acidic pH of tumor microenvironment) than\nunder a physiological pH condition. Both in vitro cytotoxicity evaluation and cell morphological\nobservation demonstrate that the therapeutic activity of dendrimer-DOX conjugates against cancer\ncells is absolutely related to the DOX drug released. More importantly, the FA conjugation onto\nthe dendrimers allowed a specific targeting to cancer cells overexpressing FA receptors (FAR),\nand allowed targeted inhibition of cancer cells. The developed G5.NHAc-FA-DOX conjugates may be\nused as a promising nanodevice for targeted cancer chemotherapy.
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