title: Cyclodextrin capped gold nanoparticles as a delivery vehicle for a prodrug of cisplatin.
abstract: 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 β-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-β-cyclodextrin (βSCD), was characterized using transmission electron microscopy and absorption spectroscopy, and the density of surface-attached βSCD molecules, ∼210 βSCD/AuNP, was determined using thermogravimetric analysis. Because (13)C NMR spectra of βSCD 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 βSCD molecules on the particle were oligomerized through disulfide linkages. Determination of the binding constant, K, for the 3-βCD interaction using (1)H 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 K2 = 26.7 M(-1), the value of K for the 3-βCD interaction (1:1 stoichiometry) is 400-800 M(-1), which is lower than the value, K = 1.4 × 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.
authors.affiliation: Department of Chemistry, Syracuse University, 111 College Place, CST, Rm 1-014, Syracuse, New York 13244-4100, United States.
authors.forename: Yi
authors.initials: Y
authors.lastname: Shi
authors.forename: Jerry
authors.initials: J
authors.lastname: Goodisman
authors.forename: James C
authors.initials: JC
authors.lastname: Dabrowiak
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000737:chemistry* / Q000494:pharmacology; D003505:Cyclodextrins / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers / Q000737:chemistry*; D004354:Drug Screening Assays, Antitumor; D006046:Gold / Q000737:chemistry*; D006801:Humans; D053768:Metal Nanoparticles / Q000737:chemistry*; D015394:Molecular Structure; D009944:Organoplatinum Compounds / Q000737:chemistry / Q000494:pharmacology; D010316:Particle Size; D010984:Platinum / Q000737:chemistry / Q000494:pharmacology; D011355:Prodrugs / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013499:Surface Properties
chemical_list: D000970:Antineoplastic Agents; D003505:Cyclodextrins; D004337:Drug Carriers; D009944:Organoplatinum Compounds; D011355:Prodrugs; D010984:Platinum; D006046:Gold; D002945:Cisplatin