title: Effectively delivering a unique hsp90 inhibitor using star polymers.
abstract: We report the synthesis of a novel heat shock protein 90 (hsp90) inhibitor conjugated to a star polymer. Using reversible addition-fragmentation chain-transfer (RAFT) polymerization, we prepared star polymers comprised of PEG attached to a predesigned functional core. The stars were cross-linked using disulfide linkers, and a tagged version of our hsp90 inhibitor was conjugated to the polymer core to generate nanoparticles (14 nM). Dynamic light scattering showed that the nanoparticles were stable in cell growth media for 5 days, and HPLC analysis of compound-release at 3 different pH values showed that release was pH dependent. Cell cytotoxicity studies and confocal microscopy verify that our hsp90 inhibitor was delivered to cells using this nanoparticle delivery system. Further, delivery of our hsp90 inhibitor using star polymer induces apoptosis by a caspase 3-dependent pathway. These studies show that we can deliver our hsp90 inhibitor effectively using star polymers, and induce apoptosis by the same pathway as the parent compound.
authors.affiliation: Department of Chemistry, University of New South Wales, Sydney, NSW 2052 Australia.
authors.forename: Seong Jong
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Department of Chemistry, University of New South Wales, Sydney, NSW 2052 Australia.
authors.forename: Deborah M
authors.initials: DM
authors.lastname: Ramsey
authors.affiliation: Australian Centre for Nanomedicine, University of New South Wales, Sydney, NSW 2052 Australia.
authors.forename: Cyrille
authors.initials: C
authors.lastname: Boyer
authors.affiliation: Australian Centre for Nanomedicine, University of New South Wales, Sydney, NSW 2052 Australia.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Davis
authors.affiliation: Department of Chemistry, University of New South Wales, Sydney, NSW 2052 Australia.
authors.forename: Shelli R
authors.initials: SR
authors.lastname: McAlpine
keywords: Heat shock protein 90; cyclic peptides; drug delivery; drug-peptide conjugation; hsp90; macrocycles; nanoparticles; polymers; star polymer