Self-Assembling Doxorubicin–Tocopherol Succinate Prodrug as a New Drug Delivery System: Synthesis, Characterization, and in Vitro and in Vivo Anticancer Activity

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• 作者：Nicolas Duhem ; Fabienne Danhier ; Vincent Pourcelle ; Jean-Marc Schumers ; Olivier Bertrand ; Cécile S. LeDuff ; Stephanie Hoeppener ; Ulrich S. Schubert ; Jean-Fran?ois Gohy ; Jacqueline Marchand-Brynaert ; Véronique Préat
• 刊名：Bioconjugate Chemistry
• 出版年：2014
• 出版时间：January 15, 2014
• 年：2014
• 卷：25
• 期：1
• 页码：72-81
• 全文大小：440K
• ISSN：1520-4812

文摘

Self-assembled prodrugs forming nanoaggregates are a promising approach to enhance the antitumor efficacy and to reduce the toxicity of anticancer drugs. To achieve this goal, doxorubicin was chemically conjugated to d-伪-tocopherol succinate through an amide bond to form N-doxorubicin鈭捨?d-tocopherol succinate (N-DOX鈥揟OS). The prodrug self-assembled in water into 250 nm nanostructures when stabilized with d-伪-tocopherol poly(ethylene glycol) 2000 succinate. Cryo-TEM analysis revealed the formation of nanoparticles with a highly ordered lamellar inner structure. NMR spectra of the N-DOX鈥揟OS nanoparticles indicated that N-DOX鈥揟OS is located in the core of the nanoparticles while PEG chains and part of the tocopherol are in the corona. High drug loading (34% w/w) and low in vitro drug release were achieved. In vitro biological assessment showed significant anticancer activity and temperature-dependent cellular uptake of N-DOX鈥揟OS nanoparticles. In vivo, these nanoparticles showed a greater antitumor efficacy than free DOX. N-DOX鈥揟OS nanoparticles might have the potential to improve DOX-based chemotherapy.