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.

A cisplatin slow-release hydrogel drug delivery system based on a formulation of the macrocycle cucurbit[7]uril, gelatin and polyvinyl alcohol

“…Previously, we found in other in vitro experiments no difference in cytotoxicity between free cisplatin and cisplatin@CB [7] when tested in vitro and a difference was only observed when the two were compared in vivo. The in vitro results here for the hydrogels containing either free cisplatin or cisplatin@CB [7] are therefore consistent with other in vitro results reported [29].…”

“…Because of the slow release nature of the hydrogels, their effect on tumour growth delay was monitored over a period of two weeks rather than one week as was previously undertaken in earlier work compared to the effectiveness of cisplatin@CB [7] and free cisplatin by intraperitoneal administration [29]. In this current work, and because the xenograft is highly cisplatin resistant, a high intraperitoneal dose of cisplatin (150 µg per animal) was needed to delay tumour growth significantly (tumour grew to only 42% size of the control tumours over the same time period).…”

“…1)[23] provides a number of benefits, including: a slower rate of reaction with sulfur containing peptides (i.e. glutathione) [24][25][26], physical stability [27], decreased side-effects [28], increased in vitro and in vivo effectiveness [28] and an ability to overcome cisplatin acquired resistance [29].…”

“…In this paper we sought to combine the slow release benefit of hydrogels with the ability of cucurbit [7]uril encapsulated cisplatin (cisplatin@CB [7]) to overcome acquired cisplatin resistance [29] as a two-fold drug delivery system. Here we report the synthesis and effectiveness of PVA and gelatin-based hydrogel slow release systems for cisplatin@CB [7].…”

Synthetic and Bioinspired Cage Nanoparticles for Drug Delivery

“…Cisplatin, a platinum-based anticancer drug that causes severe side effects, could form an inclusion complex with CB [7], stabilized by four hydrogen bonds while retaining its activity [114]. In addition, cisplatin@CB [7] complex allowed to circumvent drug resistance in vivo in ovarian tumor xenografts.…”