Tuning drug release from polyoxazoline-drug conjugates
Harris, J. Milton and Bentley, Michael D. and Moreadith, Randall W. and Viegas, Tacey X. and Fang, Zhihao and Yoon, Kunsang and Weimer, Rebecca and Dizman, Bekir and Nordstiern, Lars (2019) Tuning drug release from polyoxazoline-drug conjugates. European Polymer Journal, 120 . ISSN 0014-3057 (Print) 1873-1945 (Online)
Official URL: http://dx.doi.org/10.1016/j.eurpolymj.2019.109241
Poly(2-oxazoline)-drug conjugates with drugs attached via releasable linkages are being developed for drug delivery. Such conjugates with pendent ester linkages that covalently bind drugs to the polymer backbone exhibit significantly slower hydrolytic release rates in plasma than the corresponding PEG- and dextran-drug conjugates. The slow drug release rates in-vitro of these POZ-drug conjugates contribute to extended in-vivo pharmacokinetic profiles. In some instances, the release kinetics may be relatively sustained and ideal for once-a week subcutaneous injection, whereas the native drug by itself may only have an in-vivo half-life of a few hours. The origin of this unusual kinetic and pharmacokinetic behavior is proposed here to involve folding of the POZ conjugate such that the relatively hydrophobic drug forms a central core, and the relatively hydrophilic polymer wraps around the core and slows enzymatic attack on the drug-polymer chemical linkage. Here we present evidence supporting this hypothesis and demonstrate how the hypothesis can be used to tune hydrolytic release rates and pharmacokinetics. Evidence for the folding hypothesis is taken from hydrolysis kinetics of a range of drugs in plasma, pharmacokinetics of a range of drugs following subcutaneous injection in laboratory animals, and nuclear magnetic resonance (NMR) studies showing folding of the POZ-rotigotine molecule. The drugs included in this study to test the hypothesis are: rotigotine, buprenorphine, dexanabinol, cannabidiol (CBD), Δ9-tetrahydrocannabinol (THC) and cannabigerol (CBG).
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