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Doxorubicin-Conjugated PAMAM Dendrimers for pH-Responsive Drug Release and Folic Acid-Targeted Cancer Therapy

By Mengen Zhang, Jingyi Zhu, Yun Zheng, Rui Guo, Shige Wang, Serge Mignani, Anne-Marie Caminade, Jean-Pierre Majoral and Xiangyang Shi

Abstract

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

Topics: PAMAM dendrimer, doxorubicin, cis-aconityl linkage, pH-responsive release, targeted cancer therapy, Pharmacy and materia medica, RS1-441
Publisher: MDPI AG
Year: 2018
DOI identifier: 10.3390/pharmaceutics10030162
OAI identifier: oai:doaj.org/article:4543f2feff6d4a45adaf751a790f0fd4
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