title: Well-Defined Polymer-Paclitaxel Prodrugs by a Grafting-from-Drug Approach.
abstract: We report on the design of a polymeric prodrug of the anticancer agent paclitaxel (PTX) by a grafting-from-drug approach. A chain transfer agent for reversible addition fragmentation chain transfer (RAFT) polymerization was efficiently and regioselectively linked to the C2' position of paclitaxel, which is crucial for its bioactivity. Subsequent RAFT polymerization of a hydrophilic monomer yielded well-defined paclitaxel-polymer conjugates with high drug loading, water solubility, and stability. The versatility of this approach was further demonstrated by ω-end post-functionalization with a fluorescent tracer. In vitro experiments showed that these conjugates are readily taken up into endosomes where native PTX is efficiently cleaved off and then reaches its subcellular target. This was confirmed by the cytotoxicity profile of the conjugate, which matches those of commercial PTX formulations based on mere physical encapsulation.
authors: Biopharmaceutical Technology Unit, Department of Pharmaceutics, Ghent University, Ghent, Belgium.
authors: Benoit
authors: B
authors: Louage
authors: Biopharmaceutical Technology Unit, Department of Pharmaceutics, Ghent University, Ghent, Belgium.
authors: Lutz
authors: L
authors: Nuhn
authors: Laboratory of Medicinal Chemistry, Department of Pharmaceutics, Ghent University, Ghent, Belgium.
authors: Martijn D P
authors: MD
authors: Risseeuw
authors: Biopharmaceutical Technology Unit, Department of Pharmaceutics, Ghent University, Ghent, Belgium.
authors: Nane
authors: N
authors: Vanparijs
authors: Biopharmaceutical Technology Unit, Department of Pharmaceutics, Ghent University, Ghent, Belgium.
authors: Ruben
authors: R
authors: De Coen
authors: Laboratory of Medicinal Chemistry, Department of Pharmaceutics, Ghent University, Ghent, Belgium.
authors: Izet
authors: I
authors: Karalic
authors: Laboratory of Medicinal Chemistry, Department of Pharmaceutics, Ghent University, Ghent, Belgium.
authors: Serge
authors: S
authors: Van Calenbergh
authors: Biopharmaceutical Technology Unit, Department of Pharmaceutics, Ghent University, Ghent, Belgium. br.degeest@ugent.be.
authors: Bruno G
authors: BG
authors: De Geest
mesh_terms: D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D009369:Neoplasms / Q000188:drug therapy; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D058105:Polymerization; D011108:Polymers / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D012995:Solubility
chemical_list: D011108:Polymers; D011355:Prodrugs; D017239:Paclitaxel
keywords: RAFT polymerization; cancer; nanotechnology; paclitaxel; prodrugs