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. 2020 Jan 12;10(5):2215-2228.
doi: 10.7150/thno.40146. eCollection 2020.

CEST MRI Detectable Liposomal Hydrogels for Multiparametric Monitoring in the Brain at 3T

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Free PMC article

CEST MRI Detectable Liposomal Hydrogels for Multiparametric Monitoring in the Brain at 3T

Xiongqi Han et al. Theranostics. .
Free PMC article

Abstract

Adjuvant treatment using local drug delivery is applied in treating glioblastoma multiforme (GBM) after tumor resection. However, there are no non-invasive imaging techniques available for tracking the compositional changes of hydrogel-based drug treatment. Methods: We developed Chemical Exchange Saturation Transfer Magnetic Resonance Imaging (CEST MRI) detectable and injectable liposomal hydrogel to monitor these events in vivo at 3T clinical field. Mechanical attributes of these hydrogels and their in vitro and in vivo CEST imaging properties were systematically studied. Results: The MRI detectable hydrogels were capable of generating multiparametric readouts for monitoring specific components of the hydrogel matrix simultaneously and independently. Herein, we report, for the first time, CEST contrast at -3.4 ppm provides an estimated number of liposomes and CEST contrast at 5 ppm provides an estimated amount of encapsulated drug. CEST contrast decreased by 1.57% at 5 ppm, while the contrast at -3.4 ppm remained constant over 3 d in vivo, demonstrating different release kinetics of these components from the hydrogel matrix. Furthermore, histology analysis confirmed that the CEST contrast at -3.4 ppm was associated with liposome concentrations. Conclusion: This multiparametric CEST imaging of individual compositional changes in liposomal hydrogels, formulated with clinical-grade materials at 3T and described in this study, has the potential to facilitate the refinement of adjuvant treatment for GBM.

Keywords: CEST MRI; glioblastoma; hydrogel; liposome.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interest exists.

Figures

Figure 1
Figure 1
Frequency sweep measurements and scanning electron microscopy (SEM) images of alginate hydrogel. (A), (B) and (C), (D) are 1 wt% alginate hydrogels with 40% and 80% crosslinking; (E), (F) and (G), (H) are 2 wt% alginate hydrogels with 40% and 80% crosslinking. Ag-I and Ag-II are alginate hydrogels with 40% and 80% crosslinking, respectively. The measurements for each sample were performed three times. Scale bar = 200 μm.
Figure 2
Figure 2
Frequency sweep measurements and scanning electron microscopy (SEM) images of HAMC hydrogel. (A) frequency sweep measurements. (B) and (C) are representative morphologies of HAMC hydrogel without and with liposomes. The measurements for each sample were performed 3 times. Scale bar = 50 μm.
Figure 3
Figure 3
B1 optimization and CEST properties of BA-liposomes (BAL, n=3). (A), (B), and (C) are Z-spectra and corresponding CEST contrasts of BAL (with 75 mg/mL lipids) under various B1 powers; (D), (E) and (F) are Z-spectra, corresponding CEST contrast, and maps at 5 ppm and -3.4 ppm of various BAL formulations.
Figure 4
Figure 4
CEST properties of liposomal hydrogels (n=3). (A) and (B) are Z-spectra, corresponding CEST contrasts, and parametric maps of liposomal alginate and HAMC hydrogels.
Figure 5
Figure 5
In vivo CEST of transplanted Lipo-Alg hydrogel. (A) T2 anatomical images of hydrogels in the brain; (B) and (C) CEST maps of the liposomal hydrogel at 5.0 ppm and -3.4 ppm; (D) and (E) are longitudinal measurements of Z-spectra and corresponding CEST contrast under 1.2 and 0.8 μT, respectively.
Figure 6
Figure 6
In vivo CEST of transplanted alginate (Alg) hydrogel. (A) T2 anatomical images of hydrogels in the brain; (B) and (C) CEST maps of Alg hydrogel at 5.0 ppm and -3.4 ppm; (D) and (E) are longitudinal measurements of Z-spectra and corresponding CEST contrast under 1.2 and 0.8 μT, respectively.
Figure 7
Figure 7
Longitudinal comparison of the CEST contrast of transplanted hydrogels in vivo. (A) CEST contrast at 5.0 ppm of implanted liposomal hydrogel versus the contralateral region at respective time-points; (B) CEST contrast at -3.4 ppm of implanted liposomal hydrogel versus Alg gel and the contralateral region at respective time-points. Significance level was set at **p < 0.01, ***p < 0.001 and ****p < 0.0001 by comparison between the samples at each time point. Values shown are means ± SD (n = 5).
Figure 8
Figure 8
Fluorescence images of the brain tissue slices. (A) and (B) are fluorescence images after 4 h and 3 d post hydrogel implantation under different channels. DAPI used for cell nucleus staining shows blue fluorescence. The rhodamine B labeled liposomal hydrogel shows red fluorescence. Scale bar = 200 μm.

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