Crown ethers are cyclic molecules consisting of a ring containing several ether groups. The most common and important members of this series are 12-crown-4 (12C4), 15-crown-5 (15C5), and 18-crown-6 (18C6). These container molecules have the ability to sequester metal ions, and their complexes with drugs are able to traverse cell membranes. This study investigated 12C4, 15C5, and 18C6 for their ability to increase solubility of ocular drugs and enhance their penetration into the cornea. Phase solubility analysis determined crown ethers' ability to enhance the solubility of riboflavin, a drug used for the therapy of keratoconus, and these solutions were investigated for ocular drug permeation enhancing properties. Atomic absorption spectroscopy demonstrated crown ether solutions' ability to sequester Ca from corneal epithelia, and crown ether mediated adsorption of riboflavin into the stroma was investigated. Induced corneal opacity studies assessed potential toxicity of crown ethers. Crown ethers enhanced riboflavin's aqueous solubility and its penetration into in vitro bovine corneas; the smaller sized crown ethers gave greatest enhancement. They were shown to sequester Ca ions from corneal epithelia; doing so loosens cellular membrane tight junctions thus enhancing riboflavin penetration. Induced corneal opacity was similar to that afforded by benzalkonium chloride and less than is produced using polyaminocarboxylic acids. However, in vivo experiments performed in rats with 12C4 did not show any statistically significant permeability enhancement compared to enhancer-free formulation.
We have previously reported the synthesis of a poly(ethylene glycol)-haloperidol (PEGhaloperidol) conjugate that retained affinity for its target D2 receptor and was stable in simulated physiological conditions. We hypothesised that this polymer-drug conjugate would localise haloperidol's activity either centrally or peripherally, dependent on the location of administration, due to the polymer preventing penetration through the blood-brain barrier (BBB). Herein, we validate this hypothesis using in vitro and in vivo studies. We first demonstrate, via a [ 35 S]GTPγS-binding assay, that drug activity is retained after conjugation to the polymer, supportive of retention of effective therapeutic ability. Specifically, the PEGhaloperidol conjugate (at 10 and 100 nM) was able to significantly inhibit dopamine-induced G-protein activation via D2 receptors, albeit with a loss of potency compared to the free haloperidol (~18-fold at 10 nM). This loss of potency was further probed and rationalised using molecular docking experiments, which indicated that conjugated haloperidol can still bind to the D2 receptors, albeit with a flipped orientation in the biding pocket within the receptor, which may explain the reduced activity. Finally, rat catalepsy studies confirmed the restricted permeation of the conjugate through the BBB in vivo. Rats treated intravenously with free haloperidol became cataleptic, whereas normal behaviour was observed in rats that received the PEG-haloperidol conjugate, suggesting that conjugation can effectively prevent unwanted central effects. Taken together these results demonstrate that conjugating small
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.