Tuning drug release from polyoxazoline-drug conjugates
Journal article, 2019

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), Delta(9)-tetrahydrocannabinol (THC) and cannabigerol (CBG).

Poly(2-ethyl-2-oxazoline) or PEOZ

Poly(2-oxazoline) or POZ

Drug delivery

Degradable ester linkages

Phenolic drugs

Pendent drugs

Pharmacokinetics

Author

J. Milton Harris

Serina Therapeutics Inc.

Michael D. Bentley

Serina Therapeutics Inc.

Randall W. Moreadith

Serina Therapeutics Inc.

Tacey X. Viegas

Serina Therapeutics Inc.

Zhihao Fang

Serina Therapeutics Inc.

Kunsang Yoon

Serina Therapeutics Inc.

Rebecca Weimer

Serina Therapeutics Inc.

Bekir Dizman

Sabanci Universitesi

Lars Nordstierna

Chalmers, Chemistry and Chemical Engineering, Applied Chemistry, Lars Nordstierna Group

European Polymer Journal

0014-3057 (ISSN)

Vol. 120 109241

Subject Categories

Pharmaceutical Sciences

Pharmacology and Toxicology

Medical Materials

DOI

10.1016/j.eurpolymj.2019.109241

More information

Latest update

1/16/2020