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

• Published in: Bioconjugate chemistry Vol. 25; no. 1; pp. 72 - 81
• Main Authors: Duhem, Nicolas, Danhier, Fabienne, Pourcelle, Vincent, Schumers, Jean-Marc, Bertrand, Olivier, LeDuff, Cécile S, Hoeppener, Stephanie, Schubert, Ulrich S, Gohy, Jean-François, Marchand-Brynaert, Jacqueline, Préat, Véronique
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 15.01.2014; Amer Chemical Soc
• Subjects: alpha-Tocopherol - chemistry; alpha-Tocopherol - pharmacology; Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Biochemical Research Methods; Biochemistry & Molecular Biology; Cell Line, Tumor; Cell Proliferation - drug effects; Chemistry; Chemistry, Multidisciplinary; Chemistry, Organic; Chemotherapy; Dose-Response Relationship, Drug; Doxorubicin - chemistry; Doxorubicin - pharmacology; Drug Delivery Systems; Drug Screening Assays, Antitumor; Humans; Life Sciences & Biomedicine; MCF-7 Cells; Mice; Mice, Inbred BALB C; Molecular Structure; Nanoparticles; Nanostructures - chemistry; Neoplasms, Experimental - drug therapy; Neoplasms, Experimental - pathology; NMR; Nuclear magnetic resonance; Physical Sciences; Polyethylene glycol; Prodrugs - chemical synthesis; Prodrugs - chemistry; Prodrugs - pharmacology; Science & Technology; Structure-Activity Relationship; Toxicity; FORMING NANOPARTICLES; CONJUGATION; DISPERSIONS; SQUALENOYLATION; NANOMEDICINE; CARRIERS; CYTOTOXICITY; CANCER-THERAPY; GEMCITABINE; VITAMIN-E TPGS
• ISSN: 1043-1802; 1520-4812; 1520-4812
• DOI: 10.1021/bc400326y

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-α-tocopherol succinate through an amide bond to form N-doxorubicin−α-d-tocopherol succinate (N-DOX–TOS). The prodrug self-assembled in water into 250 nm nanostructures when stabilized with d-α-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–TOS nanoparticles indicated that N-DOX–TOS 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–TOS nanoparticles. In vivo, these nanoparticles showed a greater antitumor efficacy than free DOX. N-DOX–TOS nanoparticles might have the potential to improve DOX-based chemotherapy.