title: Controlling drug release from non-aqueous environments: Moderating delivery from ocular silicone oil drug reservoirs to combat proliferative vitreoretinopathy.
abstract: In a number of cases of retinal detachment, treatment may require the removal of the vitreous humour within the eye and replacement with silicone oil to aid healing of the retina. The insertion of silicone oil offers the opportunity to also deliver drugs to the inside of the eye; however, drug solubility in silicone oil is poor and release from this hydrophobic drug reservoir is not readily controlled. Here, we have designed a range of statistical graft copolymers that incorporate dimethylsiloxane and ethylene glycol repeat units within the side chains, allowing short chains of oligo(ethylene glycol) to be solubilised within silicone oil and provide hydrogen bond acceptor sites to interact with acid functional drug molecules. Our hypothesis included the potential for such interactions to be able to delay/control drug release and for polymer architecture and composition to play a role in the silicone oil miscibility of the targeted polymers. This strategy has been successfully demonstrated using both ibuprofen and all-trans retinoic acid; drugs with anti-inflammatory and anti-proliferation activity. After the copolymers were shown to be non-toxic to retinal pigment epithelial cells, studies of drug release using radiochemical approaches showed that the presence of 10v/v% of a linear graft copolymer could extend ibuprofen release over three-fold (from 3days to >9days) whilst the release of all-trans retinoic from the silicone oil phase was extended to >72days. These timescales are highly clinically relevant showing the potential to tune drug delivery during the healing process and offer an efficient means to improve patient outcomes.
authors.affiliation: Department of Chemistry, University of Liverpool, Crown Street, L69 7ZD, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Cauldbeck
authors.affiliation: Department of Chemistry, University of Liverpool, Crown Street, L69 7ZD, UK; Department of Eye and Vision Science, University of Liverpool, Liverpool, UK.
authors.forename: Maude
authors.initials: M
authors.lastname: Le Hellaye
authors.affiliation: Unilever Research Centre, Port Sunlight, Quarry Road East, Bebington, Wirral CH63 3JW, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Long
authors.affiliation: Department of Eye and Vision Science, University of Liverpool, Liverpool, UK.
authors.forename: Stephnie M
authors.initials: SM
authors.lastname: Kennedy
authors.affiliation: Department of Eye and Vision Science, University of Liverpool, Liverpool, UK.
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Williams
authors.affiliation: Department of Eye and Vision Science, University of Liverpool, Liverpool, UK. Electronic address: vkearns@liverpool.ac.uk.
authors.forename: Victoria R
authors.initials: VR
authors.lastname: Kearns
authors.affiliation: Department of Chemistry, University of Liverpool, Crown Street, L69 7ZD, UK. Electronic address: srannard@liverpool.ac.uk.
authors.forename: Steve P
authors.initials: SP
authors.lastname: Rannard
mesh_terms: D060433:Administration, Ophthalmic; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D004129:Dimethylpolysiloxanes / Q000737:chemistry; D004337:Drug Carriers; D065546:Drug Liberation; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D007052:Ibuprofen / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D011092:Polyethylene Glycols / Q000737:chemistry; D055213:Retinal Pigment Epithelium / Q000166:cytology / Q000187:drug effects; D012827:Silicone Oils / Q000737:chemistry*; D012997:Solvents; D014212:Tretinoin / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D018630:Vitreoretinopathy, Proliferative / Q000188:drug therapy*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D004129:Dimethylpolysiloxanes; D004337:Drug Carriers; D012827:Silicone Oils; D012997:Solvents; D011092:Polyethylene Glycols; D014212:Tretinoin; C013830:baysilon; D007052:Ibuprofen
keywords: Graft copolymer; Hydrogen bonding; Non-polar drug reservoir, ocular drug delivery; RAFT polymerization; Silicone oil