Aqueous solutions of some polymers exhibit a lower critical solution temperature (LCST); that is, they form phase-separated aggregates when heated above a threshold temperature. Such polymers found many promising (bio)medical applications, including in situ thermogelling with controlled drug release, polymer-supported radiotherapy (brachytherapy), immunotherapy, and wound dressing, among others. Yet, despite the extensive research on medicinal applications of thermoresponsive polymers, their biodistribution and fate after administration remained unknown. Thus, herein, they studied the pharmacokinetics of four different thermoresponsive polyacrylamides after intramuscular administration in mice. In vivo, these thermoresponsive polymers formed depots that subsequently dissolved with a two-phase kinetics (depot maturation, slow redissolution) with half-lives 2 weeks to 5 months, as depot vitrification prolonged their half-lives. Additionally, the decrease of TCP of a polymer solution increased the density of the intramuscular depot. Moreover, they detected secondary polymer depots in the kidneys and liver; these secondary depots also followed two-phase kinetics (depot maturation and slow dissolution), with half-lives 8 to 38 days (kidneys) and 15 to 22 days (liver). Overall, these findings may be used to tailor the properties of thermoresponsive polymers to meet the demands of their medicinal applications. Their methods may become a benchmark for future studies of polymer biodistribution.

Center for Advanced Preclinical Imaging 1st Faculty of Medicine Charles University Salmovská 3 Prague 2 Prague 120 00 Czech Republic

Department of Organic and Macromolecular Chemistry Centre of Macromolecular Chemistry Ghent University Krijgslaan 281 S4 Ghent 9000 Belgium

Department of Physical and Macromolecular Chemistry Faculty of Sciences Charles University Hlavova 8 Prague 2 Prague 128 00 Czech Republic

FUJIFILM VisualSonics Inc Joop Geesinkweg 140 1114 AB Amsterdam The Netherlands

Institute of Biophysics and Informatics Charles University 1st Faculty of Medicine Salmovská 1 Prague 2 Prague 120 00 Czech Republic

Institute of Histology and Embryology 1st Faculty of Medicine Charles University Albertov 4 Prague 2 Prague 128 00 Czech Republic

Institute of Macromolecular Chemistry Czech Academy of Sciences Heyrovského náměstí 2 Prague 6 Prague 162 06 Czech Republic

Institute of Organic Chemistry and Biochemistry Czech Academy of Sciences Flemingovo náměstí 542 Prague 6 Prague 160 00 Czech Republic

Weizmann Institute of Science Department of Brain Sciences Rehovot 7610001 Israel

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