title: Cholesterol-poly(ethylene) glycol nanocarriers for the transscleral delivery of sirolimus.
abstract: The aim of this study was to prepare and characterize cholesterol-poly(ethylene) glycol (chol-PEG) nanocarriers of two different molecular weights (1 and 5 kDa) and to determine their effect on the transscleral retention and permeation of a lipophilic multi-therapeutic agent, sirolimus (rapamycin), with potential application in angiogenic and immunogenic ocular diseases. Sirolimus-containing nanocarriers were prepared using the thin-film hydration method and characterized for their physicochemical properties including size, drug entrapment (EE) and loading (DL) efficiencies, stability, surface charge, morphology, critical micelle concentration (CMC) and thermal properties. Ussing chambers were used to determine the retention and permeability of sirolimus-containing nanocarriers in porcine sclera followed by ultrastructural tissue examination. Sirolimus-containing nanocarriers had an average size of 11.7 nm (chol-PEG 1 kDa) and 13.8 nm (chol-PEG 5 kDa) and zeta potentials of 0.41 and -1.05, respectively. Both nanocarriers had similar transscleral permeabilities (chol-PEG 1 kDa 6.44 × 10(-7) and 5 kDa 6.16 × 10(-7) cm2 s(-1)), and very high scleral retention compared with a free solution of sirolimus (chol-PEG 1 kDa 16.9 μg/g; chol-PEG 5 kDa 7.48 μg/g; free sirolimus 0.57 μg/g). The DL (EE) for chol-PEG 1 and 5 kDa were 2.93% (77.4%) and 3.10% (81.6%), respectively. The CMC values for the nanocarriers were similar to those previously reported in literature (3.85 × 10(-7) M for chol-PEG 1 kDa; 4.26 × 10(-7) M for chol-PEG 5 kDa). In conclusion, chol-PEG nanocarriers successfully loaded sirolimus and resulted in scleral permeation and high retention, which shows potential utility for the topical delivery of lipophilic ocular drugs.
authors: University College London School of Pharmacy, London, United Kingdom.
authors: Naba
authors: N
authors: Elsaid
authors: University College London School of Pharmacy, London, United Kingdom. Electronic address: s.somavarapu@ucl.ac.uk.
authors: Satyanarayana
authors: S
authors: Somavarapu
authors: King's College London, London, United Kingdom; King's College Hospital, London, United Kingdom. Electronic address: t.jackson1@nhs.net.
authors: Timothy L
authors: TL
authors: Jackson
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D002152:Calorimetry, Differential Scanning; D002626:Chemistry, Pharmaceutical; D002784:Cholesterol / Q000031:analogs & derivatives* / Q000737:chemistry; D004337:Drug Carriers / Q000737:chemistry*; D004355:Drug Stability; D008823:Micelles; D008855:Microscopy, Electron, Scanning; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D010316:Particle Size; D010539:Permeability; D004364:Pharmaceutical Preparations; D011092:Polyethylene Glycols / Q000737:chemistry*; D033362:Powder Diffraction; D012590:Sclera / Q000378:metabolism* / Q000648:ultrastructure; D020123:Sirolimus / Q000008:administration & dosage* / Q000493:pharmacokinetics; D013552:Swine
chemical_list: D000900:Anti-Bacterial Agents; D004337:Drug Carriers; D008823:Micelles; D004364:Pharmaceutical Preparations; C118255:polyethylene glycol-cholesterol; D011092:Polyethylene Glycols; D002784:Cholesterol; D020123:Sirolimus
keywords: age-related macular degeneration; cholesterol poly(ethylene) glycol; micelle; permeation; rapamycin; sclera; sirolimus