Reduction-sensitive tioguanine prodrug micelles

André J. Van Der Vlies, Urara Hasegawa, Jeffrey A. Hubbell

Research output: Contribution to journalArticle

22 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2812-2818
Number of pages7
JournalMolecular Pharmaceutics
Volume9
Issue number10
DOIs
StatePublished - Dec 3 2012

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery

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    Van Der Vlies, A. J., Hasegawa, U., & Hubbell, J. A. (2012). Reduction-sensitive tioguanine prodrug micelles. Molecular Pharmaceutics, 9(10), 2812-2818. https://doi.org/10.1021/mp3001183