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Controlled Cerebral Delivery of Proteins: MRI-Based Monitoring of In Vitro and In Vivo Protein Release |\n| --- | --- |\n| Authors | Yanev, Pavel; van Tilborg , Geralda A. F. ; Boere , Kristel W. M. ; Stowe , Ann M. ; van der Toorn , Annette; Viergever, Max A. ; Hennink , Wim E. ; Vermonden , Tina; Dijkhuizen, Rick M. |\n| Published in | ACS Biomaterials Science and Engineering |\n| Publication Date | 2023-02-13 |\n| Link | [http://hdl.handle. net/1874/427650](http://hdl.handle. net/1874/427650) |\n| Citation | Yanev, P, van Tilborg , G A F, Boere , K W M , Stowe , A M , van der Toorn ,\u003Cbr>A , Viergever, M A , Hennink , W E , Vermonden , T & Dijkhuizen , R M 2023 ,'Thermosensitive Biodegradable Hydrogels for Local and Controlled Cerebral Delivery of Proteins : MRI-Based Monitoring of In Vitro and In Vivo Protein Release ' , ACS Biomaterials Science and Engineering , vol. 9 , no. 2 , pp. 760-772. [https://doi.org/10.1021/acsbiomaterials.2c01224](https://doi.org/10.1021/acsbiomaterials.2c01224) |\n| Versions / License | Publisher version |\n| Rights | [https://www. uu. nl/en/university-library/license-and-reuse-conditions](https://www. uu. nl/en/university-library/license-and-reuse-conditions) |\n\n[pubs.acs.org/journal/abseba](pubs.acs.org/journal/abseba)  Article   \nThermosensitive Biodegradable Hydrogels for Local and Controlled Cerebral Delivery of Proteins: MRI-Based Monitoring of In Vitro and In Vivo Protein Release  \nPavel Yanev, Geralda A.F. van Tilborg, * Kristel W. M. Boere, Ann M. Stowe, Annette van der Toorn, Max A. Viergever, Wim E. Hennink, Tina Vermonden, and Rick M. Dijkhuizen  \n Cite This: ACS Biomater. Sci. Eng. 2023, 9, 760−772  \nRead Online  \nDownloaded via UTRECHT UNIV on April 3, 2023 at 11:24:43 (UTC) . See [https://pubs.acs.org/sharingguidelines](https://pubs.acs.org/sharingguidelines) for options on how to legitimately share published articles.  \nACCESS  \n Metrics & More  \n Article Recommendations  \n*sı   \nSupporting Information  \nABSTRACT: Hydrogels have been suggested as novel drug delivery systems for sustained release of therapeutic proteins in various neurological disorders. The main advantage these systems offer is the controlled, prolonged exposure to a therapeutically effective dose of the released drug after a single intracerebral injection. Characterization of controlled release of therapeutics from a hydrogel is generally performed in vitro, as current methods do not allow for in vivo measurements of spatiotemporal distribution and release kinetics of a loaded protein. Importantly, the in vivo environment introduces many additional variables and factors that cannot be effectively simulated under in vitro conditions. To address this, in the present contribution, we developed a noninvasive in vivo magnetic resonance imaging (MRI) method to monitor local protein release from two injected hydrogels of the same chemical composition but different initial water contents. We designed a biodegradable hydrogel formulation composed of low and high concentration thermosensitive polymer and thiolated hyaluronic acid, which is liquid at room temperature and forms a gel due to a combination of physical and chemical cross-linking upon injection at 37 °C. The in vivo protein release kinetics from these gels were assessed by MRI analysis utilizing a model protein labeled with an MR contrast agent, i.e. gadolinium-labeled albumin (74 kDa). As proof of principle, the release kinetics of the hydrogels were first measured with MRI in vitro. Subsequently, the protein loaded hydrogels were administered in male Wistar rat brains and the release in vivo was monitored for 21 days. In vitro, the thermosensitive hydrogels with an initial water content of 81 and 66% released 64 ± 3% and 43 ± 3% of the protein loading, respectively, during the first 6 days at 37 °C. These differences were even more profound in vivo, where the thermosensit","cbCairsUvfSlkmWq","https://ap.wps.com/l/cbCairsUvfSlkmWq","pdf",8033666,14,"English","# ABSTRACT\n## INTRODUCTION\n## Received, Accepted, Published","[{\"question\":\"What problem does the study address in protein delivery from hydrogels?\",\"answer\":\"It addresses the limitation of current characterization methods that rely on in vitro measurements and cannot effectively capture in vivo spatiotemporal distribution and release kinetics.\"},{\"question\":\"How does the study monitor protein release in vivo?\",\"answer\":\"It uses a noninvasive MRI method with a model protein labeled with an MR contrast agent (gadolinium-labeled albumin) to track local protein release from injected hydrogels.\"},{\"question\":\"What key differences were observed between in vitro and in vivo release behavior?\",\"answer\":\"In vitro, hydrogels with higher and lower initial water contents released 64 ± 3% and 43 ± 3% in the first 6 days at 37 °C, while in vivo release after one week was 83 ± 16% and 57 ± 15%, with substantial differences in gel volume changes over time.\"}]","Thermosensitive Biodegradable Hydrogels for Local and Controlled Cerebral Delivery of Proteins: MRI-Based Monitoring of In Vitro and In Vivo Protein Release | PDF",1790000936,35]