Injectable supramolecular Ureidopyrimidinone hydrogels provide sustained release of extracellular vesicle therapeutics

Emma A. Mol; Zhiyong Lei; Marieke T. Roefs; Maarten H. Bakker; Marie José Goumans; Pieter A. Doevendans; Patricia Y.W. Dankers; Pieter Vader; Joost P.G. Sluijter

doi:10.1002/adhm.201900847

Injectable supramolecular Ureidopyrimidinone hydrogels provide sustained release of extracellular vesicle therapeutics

Emma A. Mol
, Zhiyong Lei
, Marieke T. Roefs
, Maarten H. Bakker
, Marie José Goumans
, Pieter A. Doevendans
, Patricia Y.W. Dankers
, Pieter Vader
, Joost P.G. Sluijter (Corresponding author)

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

Extracellular vesicles (EVs) are small vesicles secreted by cells and have gained increasing interest as both drug delivery vehicles or as cell-free therapeutics for regenerative medicine. To achieve optimal therapeutic effects, strategies are being developed to prolong EV exposure to target organs. One promising approach to achieve this is through EV-loaded injectable hydrogels. In this study, the use of a hydrogel based on ureido-pyrimidinone (UPy) units coupled to poly(ethylene glycol) chains (UPy-hydrogel) is examined as potential delivery platform for EVs. The UPy-hydrogel undergoes a solution-to-gel transition upon switching from a high to neutral pH, allowing immediate gelation upon administration into physiological systems. Here, sustained EV release from the UPy-hydrogel measured over a period of 4 d is shown. Importantly, EVs retain their functional capacity after release. Upon local administration of fluorescently labeled EVs incorporated in a UPy-hydrogel in vivo, EVs are still detected in the UPy-hydrogel after 3 d, whereas in the absence of a hydrogel, EVs are internalized by fat and skin tissue near the injection site. Together, these data demonstrate that UPy-hydrogels provide sustained EV release over time and enhance local EV retention in vivo, which could contribute to improved therapeutic efficacy upon local delivery and translation toward new applications.

Original language	English
Article number	1900847
Number of pages	8
Journal	Advanced Healthcare Materials
Volume	8
Issue number	20
DOIs	https://doi.org/10.1002/adhm.201900847
Publication status	Published - 1 Oct 2019

Funding

The authors thank Maike Brans (UMC Utrecht), Hemse Al-Khamisi (UMC Utrecht), and Maaike Schotman (TU Eindhoven) for their excellent technical assistance and useful discussions. This work was supported by the Project EVICARE (No. 725229) of the European Research Council (ERC) to J.P.G.S. and P.Y.W.D., co-funded by the Project SMARTCARE-II of the BioMedicalMaterials institute to J.P.G.S./M.-J.G., the ZonMw-TAS program (No. 116002016) to J.P.G.S./Z.L., the Dutch Ministry of Economic Affairs, Agriculture and Innovation and the Netherlands CardioVascular Research Initiative (CVON): the Dutch Heart Foundation to J.P.G.S./M.-J.G., Dutch Federations of University Medical Centers, the Netherlands Organization for Health Research and Development, and the Royal Netherlands Academy of Sciences. P.V. was funded by a VENI fellowship (No. 13667) from the Netherlands Organisation for Scientific Research (NWO).

Keywords

controlled release
drug delivery
exosomes
extracellular vesicles
injectable hydrogels

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title = "Injectable supramolecular Ureidopyrimidinone hydrogels provide sustained release of extracellular vesicle therapeutics",

abstract = "Extracellular vesicles (EVs) are small vesicles secreted by cells and have gained increasing interest as both drug delivery vehicles or as cell-free therapeutics for regenerative medicine. To achieve optimal therapeutic effects, strategies are being developed to prolong EV exposure to target organs. One promising approach to achieve this is through EV-loaded injectable hydrogels. In this study, the use of a hydrogel based on ureido-pyrimidinone (UPy) units coupled to poly(ethylene glycol) chains (UPy-hydrogel) is examined as potential delivery platform for EVs. The UPy-hydrogel undergoes a solution-to-gel transition upon switching from a high to neutral pH, allowing immediate gelation upon administration into physiological systems. Here, sustained EV release from the UPy-hydrogel measured over a period of 4 d is shown. Importantly, EVs retain their functional capacity after release. Upon local administration of fluorescently labeled EVs incorporated in a UPy-hydrogel in vivo, EVs are still detected in the UPy-hydrogel after 3 d, whereas in the absence of a hydrogel, EVs are internalized by fat and skin tissue near the injection site. Together, these data demonstrate that UPy-hydrogels provide sustained EV release over time and enhance local EV retention in vivo, which could contribute to improved therapeutic efficacy upon local delivery and translation toward new applications.",

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AU - Bakker, Maarten H.

AU - Goumans, Marie José

AU - Doevendans, Pieter A.

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AU - Sluijter, Joost P.G.

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AB - Extracellular vesicles (EVs) are small vesicles secreted by cells and have gained increasing interest as both drug delivery vehicles or as cell-free therapeutics for regenerative medicine. To achieve optimal therapeutic effects, strategies are being developed to prolong EV exposure to target organs. One promising approach to achieve this is through EV-loaded injectable hydrogels. In this study, the use of a hydrogel based on ureido-pyrimidinone (UPy) units coupled to poly(ethylene glycol) chains (UPy-hydrogel) is examined as potential delivery platform for EVs. The UPy-hydrogel undergoes a solution-to-gel transition upon switching from a high to neutral pH, allowing immediate gelation upon administration into physiological systems. Here, sustained EV release from the UPy-hydrogel measured over a period of 4 d is shown. Importantly, EVs retain their functional capacity after release. Upon local administration of fluorescently labeled EVs incorporated in a UPy-hydrogel in vivo, EVs are still detected in the UPy-hydrogel after 3 d, whereas in the absence of a hydrogel, EVs are internalized by fat and skin tissue near the injection site. Together, these data demonstrate that UPy-hydrogels provide sustained EV release over time and enhance local EV retention in vivo, which could contribute to improved therapeutic efficacy upon local delivery and translation toward new applications.

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Injectable supramolecular Ureidopyrimidinone hydrogels provide sustained release of extracellular vesicle therapeutics

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