title: Reduction-sensitive tioguanine prodrug micelles.
abstract: Colloidal drug and prodrug conjugates have unique targeting characteristics for tumor vasculature from the blood and for the lymphatics draining a tissue injection site. Tioguanine and tioguanine-generating prodrugs have been investigated as anticancer and immunosuppressive agents, including use in cancer immunotherapy. Recently we developed block copolymers of poly(ethylene glycol)-bl-poly(propylene sulfide) that self-assemble in aqueous solutions to form micellar structures. Since the polymers carry a free terminal thiol group resulting from the ring-opening polymerization of the propylene sulfide monomer, we sought to prepare prodrug block copolymers with tioguanine linked by a reduction-sensitive disulfide bond. The synthesis involved a disulfide exchange between the oxidized form of tioguanine and the polymer. Spectroscopic data is presented to support the proposed reaction. The polymers self-assembled when dispersed in water to form tioguanine prodrug micelles with a size range between 18 and 40 nm that released tioguanine in response to cysteine and serum as shown spectroscopically. In comparison with a poly(ethylene glycol) prodrug polymer, we show that the rate of tioguanine release can be controlled by changing the poly(propylene sulfide) block length and that the tioguanine remains bioactive with cultured cells.
authors.affiliation: Institute of Bioengineering, School of Life Sciences and School of Engineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: André J
authors.initials: AJ
authors.lastname: van der Vlies
authors.forename: Urara
authors.initials: U
authors.lastname: Hasegawa
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Hubbell
mesh_terms: D045744:Cell Line, Tumor; D004220:Disulfides / Q000737:chemistry; D006367:HeLa Cells; D006801:Humans; D008546:Melanoma, Experimental; D008823:Micelles; D010084:Oxidation-Reduction; D010316:Particle Size; D011092:Polyethylene Glycols / Q000737:chemistry; D058105:Polymerization; D011108:Polymers / Q000737:chemistry; D011355:Prodrugs / Q000737:chemistry*; D013440:Sulfides / Q000737:chemistry; D013866:Thioguanine / Q000737:chemistry*; D014867:Water / Q000737:chemistry
chemical_list: D004220:Disulfides; D008823:Micelles; D011108:Polymers; D011355:Prodrugs; D013440:Sulfides; D014867:Water; C090687:propylene sulfide; D011092:Polyethylene Glycols; D013866:Thioguanine