Cyclodextrin Capped Gold Nanoparticles as a Delivery Vehicle for a Prodrug of Cisplatin

In this work, we explore the use of a quick coupling mechanism for arming a cyclodextrin coated gold nanoparticle (AuNP) delivery vehicle, 2, with an adamantane-oxoplatin conjugate that is a prodrug of cisplatin, 3, to produce a cytotoxic nanodrug, 4. The two-part arming system, which utilizes the well-known guest-host interaction between beta-cyclodextrin and adamantane, may be useful for rapidly constituting polyfunctional nanodrugs prior to their application in chemotherapy. The 4.7 +/- 1.1 nm delivery vehicle, 2, coated with per-6-thio-beta-cyclodextrin (beta SCD), was characterized using transmission electron microscopy and absorption spectroscopy, and the density of surface-attached beta SCD molecules, similar to 210 beta SCD/AuNP, was determined using thermogravimetric analysis. Because C-13 NMR spectra of beta SCD used in the study exhibited disulfide linkages and the observed surface density on the AuNP exceeded that possible for a close-packed mono layer, a fraction of the surface-attached beta SCD molecules on the particle were oligomerized through disulfide linkages. Determination of the binding constant, K, for the 3-beta CD interaction using H-1 NMR chemical shifts was complicated by the self-association of 3 to form a dimer through its conjugated adamantane residue. With a dimerization constant of K-2 = 26.7 M-1, the value of K for the 3-beta CD interaction (1:1 stoichiometry) is 400-800 M-1, which is lower than the value, K = 1.4 x 10(3) M-1, measured for the 2-3 interaction using ICP-MS. Optical microscopy showed that when neuroblastoma SK-N-SH cells are treated with the nanodrug, 4 (2+3), clusters of gold nanoparticles are observed in the nuclear regions of living cells within 24 h after exposure, but, at later times when most cells are dying or dead, clustering is no longer observed. Treating the cells with 4 for 72 h gave percent inhibitions that are lower than that of cisplatin, suggesting that the Pt(IV) ions in 4 may be incompletely reduced to cytotoxic Pt(II) species in the cell.