title: Self-assembling doxorubicin-tocopherol succinate prodrug as a new drug delivery system: synthesis, characterization, and in vitro and in vivo anticancer activity.
abstract: 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.
authors: Université catholique de Louvain , Louvain Drug Research Institute, Pharmaceutics and Drug Delivery, 73 B1.73.12 Avenue Mounier, 1200 Brussels, Belgium.
authors: Nicolas
authors: N
authors: Duhem
authors: Fabienne
authors: F
authors: Danhier
authors: Vincent
authors: V
authors: Pourcelle
authors: Jean-Marc
authors: JM
authors: Schumers
authors: Olivier
authors: O
authors: Bertrand
authors: Cécile S
authors: CS
authors: Leduff
authors: Stephanie
authors: S
authors: Hoeppener
authors: Ulrich S
authors: US
authors: Schubert
authors: Jean-François
authors: JF
authors: Gohy
authors: Jacqueline
authors: J
authors: Marchand-Brynaert
authors: Véronique
authors: V
authors: Préat
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000737:chemistry / Q000494:pharmacology*; D016503:Drug Delivery Systems; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D015394:Molecular Structure; D049329:Nanostructures / Q000737:chemistry; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D024502:alpha-Tocopherol / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D011355:Prodrugs; D004317:Doxorubicin; D024502:alpha-Tocopherol