title: Cucurbit[7]uril encapsulated cisplatin overcomes cisplatin resistance via a pharmacokinetic effect.
abstract: The cucurbit[n]uril (CB[n]) family of macrocycles has been shown to have potential in drug delivery where they are able to provide physical and chemical stability to drugs, improve drug solubility, control drug release and mask the taste of drugs. Cisplatin is a small molecule platinum-based anticancer drug that has severe dose-limiting side-effects. Cisplatin forms a host-guest complex with cucurbit[7]uril (cisplatin@CB[7]) with the platinum atom and both chlorido ligands located inside the macrocycle, with binding stabilised by four hydrogen bonds (2.15-2.44 Å). Whilst CB[7] has no effect on the in vitro cytotoxicity of cisplatin in the human ovarian carcinoma cell line A2780 and its cisplatin-resistant sub-lines A2780/cp70 and MCP1, there is a significant effect on in vivo cytotoxicity using human tumour xenografts. Cisplatin@CB[7] is just as effective on A2780 tumours compared with free cisplatin, and in the cisplatin-resistant A2780/cp70 tumours cisplatin@CB[7] markedly slows tumour growth. The ability of cisplatin@CB[7] to overcome resistance in vivo appears to be a pharmacokinetic effect. Whilst the peak plasma level and tissue distribution are the same for cisplatin@CB[7] and free cisplatin, the total concentration of circulating cisplatin@CB[7] over a period of 24 hours is significantly higher than for free cisplatin when administered at the equivalent dose. The results provide the first example of overcoming drug resistance via a purely pharmacokinetic effect rather than drug design or better tumour targeting, and demonstrate that in vitro assays are no longer as important in screening advanced systems of drug delivery.
authors.affiliation: Institute of Cancer Sciences, University of Glasgow, Cancer Research UK Beatson Laboratories, Garscube Estate, Glasgow, G61 1BD, UK. j.a.plumb@beatson.gla.ac.uk
authors.forename: Jane A
authors.initials: JA
authors.lastname: Plumb
authors.forename: Balaji
authors.initials: B
authors.lastname: Venugopal
authors.forename: Rabbab
authors.initials: R
authors.lastname: Oun
authors.forename: Natividad
authors.initials: N
authors.lastname: Gomez-Roman
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Kawazoe
authors.forename: Natarajan Sathiyamoorthy
authors.initials: NS
authors.lastname: Venkataramanan
authors.forename: Nial J
authors.initials: NJ
authors.lastname: Wheate
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D001952:Bridged-Ring Compounds / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D004337:Drug Carriers / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D023041:Xenograft Model Antitumor Assays; D047028:Macrocyclic Compounds; D000099246:Cucurbit(n)urils
chemical_list: D000970:Antineoplastic Agents; D001952:Bridged-Ring Compounds; D002945:Cisplatin; D004337:Drug Carriers; D007093:Imidazoles; C456276:cucurbit(7)uril; D047028:Macrocyclic Compounds; D000099246:Cucurbit(n)urils