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Pharmacokinetics of Intramuscularly Administered Thermoresponsive Polymers


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 have many promising (bio)medical applications, including in situ thermogelling with controlled drug-release, cell/ tissue cultures, polymer-supported radiotherapy (brachytherapy), immunotherapy, wound dressing and healing, and cell tracking, among others. Yet, despite extensive research of medicinal applications of thermoresponsive polymers, their biodistribution and fate after administration remain largely unknown. Thus, we studied the pharmacokinetics of four different thermoresponsive polyacrylamides after intramuscular administration in mice. In vivo, these thermoresponsive polymers formed depots of various densities, which subsequently dissolved with two-phase kinetics (depot maturation, slow redissolution). Their half-lives ranged from 2 weeks to 5 months, depending on their structure and thermal properties as vitrified depots led to longer half-lives. Additionally, the density of intramuscular depots increased with the decrease in the TCP of the polymer solution. Moreover, we detected secondary polymer depots in the kidneys and liver. The evolution of these secondary depots also followed a two-phase kinetics (depot maturation and slow dissolution), with half-lives ranging from 8 to 38 days (kidneys) and from 15 to 22 days (liver). Overall, our findings may be used to tailor the properties of thermoresponsive polymers to meet the demands of their medicinal applications, and our method may become a benchmark for future studies of polymer biodistribution. This article is protected by copyright. All rights reserved.


Keywords:

2-difluoroethyl)acrylamide; LCST; N-diethylacrylamide); in vivo biodistribution; poly(2; poly(N; poly(N-acryloylpyrolidine); poly(N-isopropylacrylamide); polyacrylamide; rational polymer design.



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