Developments of CEST MRI-detectable Hydrogels for Local Treatment

化學交換飽和轉移磁共振可檢測水凝膠的開發及其在局部治療中的應用

Student thesis: Doctoral Thesis

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Award date10 Sep 2020

Abstract

Hydrogels are three dimensional hydrophilic networks that have wide biomedical applications. Owing to their high-water content, porous structure, tunable mechanical properties and superior biocompatibility, hydrogels are one of the promising biomaterials for the delivery of drugs and cells. In addition to facilitate the delivery, hydrogels can provide spatial and temporal control over the release of contents. Injectable hydrogels are highly desirable, as they can be precisely injected into the anatomic location through fine needle, minimizing the invasiveness of hydrogel implant. Moreover, they can be designed to maximize the surface coverage and meet the mechanical requirements of injection sites, such as cavity after tumor resections. Currently, tools to evaluate the hydrogels after implantation are still lacking, in particular the real-time monitoring of drug distribution and physiochemical changes of hydrogel over time in vivo, such as degradation and drug release.

Chemical exchange saturation transfer (CEST) is a relatively new magnetic resonance imaging (MRI) contrast that based on the exchange between exchangeable protons of molecules and water. Under radiofrequency pulse at specific frequency, which is called saturation, the exchangeable protons can be detected via monitoring the changes in the water signal. This exchange with bulk water results in the signal amplification that enables the detection of low concentration molecules in vivo. Many molecules show inherent CEST contrast, including endogenous and exogenous molecules, as well as many chemotherapeutics. Furthermore, the frequency specific nature of CEST contrast enables identification of different exchangeable protons simultaneously and independently, making CEST superior for biomedical imaging. Hence, in this dissertation, various CEST MRI detectable and injectable hydrogels were designed and developed for the applications of local drug and cell delivery.

First, we developed CEST MRI detectable and injectable liposomal hydrogels targeted for glioblastoma (GBM) local treatment by encapsulation barbituric acid (BA, a model drug) loaded liposomes into alginate hydrogel. The mechanical properties of these hydrogels and their in vitro and in vivo CEST imaging properties were systematically studied at 3T clinical field strength MRI. The MRI detectable hydrogels were capable of generating multiparametric readouts for monitoring specific components of the hydrogel matrix simultaneously and independently. Herein, we reported, for the first time, CEST contrast at -3.4 ppm provided a semi-quantitative readout of the number of liposomes and the CEST contrast at 5 ppm provided an estimated amount of encapsulated drug. The optimized injectable liposomal hydrogel generated CEST contrast of 6.87% at 5 ppm for 75 mg/mL, and CEST contrast of 2.38 ± 0.28% at -3.4 ppm for 1.7×1016 particles/mL. We observed a different release rates of these hydrogel components after injection into the mouse brain over 3 days. This multiparametric CEST imaging of individual compositional changes in liposomal hydrogel matrix showed promises to facilitate the refinement of adjuvant local treatment for GBM.

Second, we developed injectable hydrogels for GBM treatments by encapsulating methotrexate (MTX, 1.4 and 2.6 ppm) and gemcitabine (Gem, 2.2 ppm)-loaded liposomes into alginate hydrogel. The resulting hydrogel showed compatible stiffness to the brain, sustainable and sequential drug release, and combined cytotoxicity to U87 tumor cells. Moreover, the natural exchangeable protons of the drugs and liposome vehicles generated CEST contrast 5.4% at 2.4 ppm and 5.0% at -3.6 ppm. This enabled the detection of these components, hence their release from hydrogel could be detected independently in vitro under a 3T MRI. These label free CEST MRI detectable hydrogel-based drug delivery could guide local drug delivery and inform the refinement of hydrogel formulations.

Third, we developed a series of self-healing chitosan-dextran based hydrogels (CDgels) to refine the mechanical property of injectable hydrogels for local treatments in the brain. These hydrogels are mechanically soft, and its composition can be detected via CEST-MRI. By studying the CEST contrast, we were able to show the hydrogel-drug interactions. The CEST contrast of resulting hydrogels at 1.1 ppm corresponded to the hydroxyl protons of dextran, which could indicate the crosslinking density as CEST contrast decrease with crosslinking density increase. In addition, the drug-hydrogel interactions were further studied by encapsulation of Gem, doxorubicin (DOX) and procarbazine (Pro). Compared with other drugs, Gem incorporation had less attenuation on hydrogel rheological properties and contrast. In addition to the 1.1 ppm from dextran of hydrogel, Gem-loaded hydrogel provided another contrast at 2.2 ppm, enabling the independent imaging of drug and hydrogel simultaneously using CEST. These unique properties in CEST contrast could be applied to imaging-guide local drug delivery to the brain.

Finally, we developed the injectable hyaluronic acid (HA) and methylcellulose (MC) hydrogel for regulatory T cells (Tregs) delivery in local treatment of uveitis. We designed and prepared mechanically soft injectable hydrogels to facilitate cell delivery into the vitreous humor of mouse eyes. The hydrogels showed unique CEST contrasts at 1.0 and -1.4 ppm, and high biocompatibility. The Tregs encapsulated in HAMC hydrogel was then injected into vitreous humor and CEST MRI was performed at day 0, 1 and 3. A significantly higher CEST contrast at day 3 correlated with high cell survival and better treatment outcome. Our findings demonstrated that HAMC could enhance cell survival and therapeutic efficacy of Tregs treatment for uveitis. CEST contrast at ±3.5 ppm predicts the treatment outcomes.

In conclusion, the CEST MRI detectable and injectable hydrogels would considerably benefit the development of hydrogel-based drug delivery and treatments. The CEST provides a new tool for monitoring hydrogel multiple composition changes, e.g., chemotherapeutic agents, hydrogel matrix and hydrogel-drug interaction, simultaneously and independently. Therefore, monitoring changes in CEST contrast during the course of treatment could guide the refinement of local treatments.

    Research areas

  • chemical exchange saturation transfer, magnetic resonance imaging, hydrogel, liposome, glioblastoma, local treatment, self-healing