Long-term in vivo dissolution of thermo- and pH-responsive, 19F magnetic resonance-traceable and injectable polymer implants

Abstract

¹⁹F magnetic resonance (¹⁹F MR) tracers stand out for their wide range of applications in experimental and clinical medicine, as they can be precisely located in living tissues with negligible fluorine background. This contribution demonstrates the long-term dissolution of multiresponsive fluorinated implants designed for prolonged release. Implants were detected for 14 (intramuscular injection) and 20 (subcutaneous injection) months by ¹⁹F MR at 4.7 T, showing favorable MR relaxation times, biochemical stability, biological compatibility and slow, long-term dissolution. Thus, polymeric implants may become a platform for long-term local theranostics.

Scheme 1. Synthesis of the thermoresponsive copolymer P(DFEAM-co-ImPAM-co-HEAM), which forms a solid implant in vivo upon injection followed by temperature and pH increase.

Fig. 1. Coil homogeneity measured using ¹H MRI on 4.7 T scanner in (a) coronal (b) axial and (c) sagittal planes; the color scale reflects signal attenuation (dB) – from the lowest (red) to the highest (blue).

Fig. 2. Results of phantoms' (c_pol = 70 mg mL⁻¹) ¹⁹F MR signal measured on 4.7 T scanner. (a) ¹⁹F MR spectrum of the polymer measured with 64 acquisitions (TA = 1 min 8 s) with given SNR and with fluorine signal peak at 0 ppm; (b) overlaid ¹H/¹⁹F MRI (red – ¹⁹F signal) with given ¹⁹F SNR and CNR for TA = 4 s (I) – 17 min 4 s (IV).

Fig. 3. Example of expected values of the ¹⁹F MRS signal biological half-life extrapolated from kinetics trends.

Fig. 4. Long-term in vivo¹⁹F MR measurement on a 4.7 T scanner. (a) In vivo¹⁹F MR spectrum in time with varying SNR values; polymer signal peak at 0 ppm and isoflurane signals at 36 and 43 ppm. (b) ¹⁹F MRS percentage changes of signal with subtracted noise and SNR. (c) Injection sites with 3D MRI reconstruction; overlaid ¹H (grayscale) and ¹⁹F (red) MRI of IM and SC depots in the coronal plane at various time points and (d) DCH of ¹⁹F MRI signal from injection sites. All results in (b) and (d) are expressed as a percentage of the day 0 signal (100%) and represent the signal change over time (from 1 to 21 months after administration).

Fig. 5. Histological images of injected muscle, control muscle, liver, kidney, spleen; tissue was collected 12 months after polymer administration and stained using haematoxylin & eosin (upper row; magnified 100-fold) and Verhoeff-van Gieson stain (lower row; magnified 200-fold).