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Matthew S Lawrence, Gary Ashley, Alex A Lewis, Wenzheng Hu, Rohn Brookes, Jordan Attwood, Meghan Tucker, Mike Struharik, Robin J Goody, Daniel Santi; The intravitreal pharmacokinetics of fluorophores conjugated to PEGs by noncleavable and self-cleaving linkers in nonhuman primates. Invest. Ophthalmol. Vis. Sci. 2014;55(13):5254.
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Drug conjugation to macromolecules that are well-tolerated and have long residence times presents a strategy to improve pharmacokinetics of existing and candidate ocular therapeutics. Studies were designed to establish a delivery platform that achieves tunable drug release by employing a novel “self-cleaving” linker chemistry to conjugate drugs to carrier polymers. To do so we first characterized the dependence of polyethylene glycol (PEG) pharmacokinetics on the size and branch number in the nonhuman primate eye non-invasively by fluorophotometry. This allowed selection of a PEG carrier that we then conjugated by “self-cleaving” linkers to a fluorophore that fluoresces on release, allowing modeling of drug pharmacokinetics.
The pharmacokinetics of intravitreally delivered high molecular weight PEG configurations conjugated to fluorescein by non-releasing linkers was characterized by fluorophotometry and compared to unconjugated intravitreal fluorescein, allowing minimally invasive longitudinal quantification of PEG fluorescein conjugate abundance in nonhuman primate eyes in non-terminal study designs. We then generated PEGs conjugated by differently tuned “self-cleaving” linkers to a fluorophore that fluoresces on separation from the carrier. This allowed quantification of the release of the conjugated fluorophore to model achievable drug release kinetics in fine temporal detail.
Following intravitreal delivery, high molecular weight fluorescein conjugated PEGs of different size and shape were retained in the vitreous for prolonged periods (t1/2 ~ 5 to 6 days) with no signs of adverse effects. There was little dependence of residence time on the size (20 to 80 kDa) or shape (1- to 4-branch) of PEGs. Conjugating a fluorophore to a PEG by a “self-cleaving” linker allowed further modulation of the release of the fluorphore beyond the sustained release achieved by degradation of the PEG.
PEGs behave as appropriate supports to extend the duration of drug action for up to two or three weeks. Conjugation of molecules to a carrier such as PEG by “self-cleaving” linkers allows further control of drug release, representing a promising strategy for ocular drug delivery.
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