Pharmacokinetics of Intramuscularly Administered Thermoresponsive Polymers

Abstract

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 T_CP 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.

Keywords: LCST; biodistribution; poly(2,2-difluoroethyl)acrylamide; poly(N,N-diethylacrylamide); poly(N-acryloylpyrolidine); poly(N-isopropylacrylamide); polyacrylamide; rational polymer design.

Figure 1

Chemical structures of our polymers: poly[(N‐2,2‐difluoroethyl)acrylamide] (pDFEA), poly[(N‐isopropyl)acrylamide] (pNIPAM), poly[(N,N‐diethyl)acrylamide] (pDEA), and poly[(N‐acryloyl)pyrrolidine] (pAP).

Figure 2

Cellular uptake of Dy‐505‐traced polymers into rMSC as a function of time; each polymer is shown in green (Dy505), cell membranes in red (CellMask Deep red), and nuclei in blue (Hoechst 33 342).

Figure 3

Biodistribution of our polymers (administered polymer concentration 0.10 mg µL⁻¹; volume 5.00 µL) and Cy7‐amine on the left side of mice at various timepoints after IM administration; the intensity of each polymer is normalized to its maximum; left: field of view; an asterisk (*) indicates the approximate site of injection; middle: biodistribution of our polymers with various M _n (in brackets; kg mol⁻¹); right: fluorescence intensity scale. The images show that primary depot diffuseness depends on T _CP at low polymer concentrations because polymers with a higher T _CP show an increased formation of primary intramuscular depots, with non‐aggregating pAP forming diffuse intramuscular depots regardless of molar mass. By contrast, polymers with T _CP well below body temperature (pNIPAM and pDEA) formed dense depots whose density increased with the molar mass. Lastly, pDFEA, whose T _CP is near body temperature at low polymer concentration, formed intermediately diffuse depots.

Figure 4

Biodistribution of our polymers (administered polymer concentration 0.10 mg µL⁻¹; volume 5.00 µL) or Cy7‐amine on the right side of mice (opposite the site of administration) at various timepoints after their intramuscular administration; the signal was normalized to absolute maxima of all polymers (normalization to maxima of each polymer is depicted in Figure S62, Supporting Information);^{[ 72 ]} left: field of view with the positions of the kidney (K) and liver (L) areas; middle: biodistribution of our polymers with various M _n (in kg per mol); right: fluorescence intensity scale.

Figure 5

Proposed biodistribution model (A) and plot of calculated concentrations in each compartment (B), demonstrated by the biodistribution of a model polymer as a function of time.