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Pharmaceutics 2018, 10(3), 162; https://doi.org/10.3390/pharmaceutics10030162

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

1
Key Laboratory of Science & Technology of Eco-Textile, Ministry of Education, College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai 201620, China
2
College of Materials Science and Engineering, Donghua University, Shanghai 201620, China
3
Centro de Química da Madeira (CQM), Universidade da Madeira, Campus da Penteada, 9020-105 Funchal, Portugal
4
Laboratoire de Chimie de Coordination du CNRS, 205 Route de Narbonne, BP 44099, 31077 Toulouse CEDEX 4, France
*
Author to whom correspondence should be addressed.
Received: 18 August 2018 / Revised: 11 September 2018 / Accepted: 17 September 2018 / Published: 19 September 2018
(This article belongs to the Special Issue Dendrimers in Nanomedical Applications: Update and Future Directions)
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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. View Full-Text
Keywords: PAMAM dendrimer; doxorubicin; cis-aconityl linkage; pH-responsive release; targeted cancer therapy PAMAM dendrimer; doxorubicin; cis-aconityl linkage; pH-responsive release; targeted cancer therapy
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Zhang, M.; Zhu, J.; Zheng, Y.; Guo, R.; Wang, S.; Mignani, S.; Caminade, A.-M.; Majoral, J.-P.; Shi, X. Doxorubicin-Conjugated PAMAM Dendrimers for pH-Responsive Drug Release and Folic Acid-Targeted Cancer Therapy. Pharmaceutics 2018, 10, 162.

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