Degradation and excretion of poly(2-oxazoline) based hemostatic materials

Marcel A. Boerman, Edwin A. Roozen (Corresponding author), Gerben M. Franssen, Johan C.M.E. Bender, Richard Hoogenboom, Sander C.G. Leeuwenburgh, Peter Laverman, Jan C.M. van Hest, Harry van Goor, Rosa P. Félix Lanao

Published: 01/08/2020


Poly(2-oxazoline) copolymers with hydroxyl groups and activated NHS ester moieties (NHS-POx) have recently been applied successfully in hemostatic devices [5]. An important requirement for clinical application of these polymers is to determine their clearance rate. In this study, we tested this for two NHS-POx variants with different polarities: NHS-POx 1 and 2. As degradation studies showed that the copolymers remained intact (except for the NHS ester), the carboxylic acid variants of these two polymers (P1 (NHS-POx 1) and P2 (NHS-POx 2)) were synthesized containing suitable chelators (DTPA and DOTA) for radiolabeling. To investigate the excretion pathway and potential accumulation of the polymers in specific organs, P1 and 2 were labeled with radioactive 111Indium (multiday imaging, t1/2 = 2.8 d) or 68Gallium (imaging within hours, t1/2 = 68 min) and intravenously injected in Wistar rats. The excretion of these radiolabeled polymers was studied by SPECT/CT, PET/CT and biodistribution using y-counting. The major part of the degradation products were renally excreted leaving only a small quantity of polymer present in kidneys after 7 days (%ID/g: 3.1 ± 1.1 (SPECT/CT) and 9.5 ± 0.6 (γ-counter) for P1 and%ID/g: 2.2 ± 0.5 (γ-counter) for P2. A prolonged study (14 days) on P2 demonstrated slow clearance from the kidneys. PET/CT measurements on 68Gallium labeled P2 revealed that the majority of the polymer was cleared within 10 min. No accumulation of the degradation products was observed in other organs than the kidneys. We demonstrated that the hemostatic NHS-POx polymers can indeed be effectively and timely cleared from the body. Statement of Significance: Synthetic polymers such as poly(2-oxazoline)s (POx) are of increasing interest in the biomedical field, e.g. because of their tunable structure. Recently, we have demonstrated in a pig model that side chain functionalized POx can be successfully used to stop bleedings during surgery. An essential research question remains what happens with the polymer after the bleeding has stopped. We have performed this study, as degradation and excretion of side chain functionalized POx is largely unknown. We have performed an in vitro degradation study to determine the degradation product and studied the excretion of radiolabeled degradation products in Wistar rats. In conclusion, we have demonstrated that side chain functionalized POx can be effectively cleared from a rat model.

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