A novel anhydrous preparation of PEG hydrogels enables high drug loading with biologics for controlled release applications

Ziegler, Christian E.; Graf, Moritz; Beck, Sebastian; Goepferich, Achim

doi:10.1016/j.eurpolymj.2021.110286

Cited by 10 publications

(15 citation statements)

References 39 publications

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“…Therefore, to achieve therapeutically relevant plasma levels of the therapeutic protein, a very high hydrogel volume is required . To address this problem, we established the water-free preparation of 8armPEG10k-hydrogels via the DA reaction, with which we were able to achieve a drug content of at least 15% (w/w) . However, these water-free hydrogels have to be prepared at temperatures above 40 °C and have polymerization times over 16 h and, hence, cannot be directly injected.…”

Section: Resultsmentioning

confidence: 99%

Injectable Anhydrous Poly(ethylene glycol) Polymer Liquids Form Protein Depot for Extended Controlled Release Applications Via Rapid In Situ Gelation

et al. 2023

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Water-free preparation of protein delivery systems has the potential to overcome the limitations of hydrogel depot systems such as off-target reactions, functional group hydrolysis, and limited loading capacity. However, a major roadblock in the development and use of these systems is administration as implantation is often required. In this study, we developed a biodegradable and water-free injectable protein delivery system via inverse electron demand Diels−Alder reaction between norbornene-and tetrazine-functionalized four-armed poly(ethylene glycol) macromonomers. 1:1 mixtures of these precursors gelled rapidly in situ, taking less than 11 s to reach their gelation point. Methyl substitution of tetrazine slowed the gelation time and increased the cross-linking density, whereas oxygen incorporation into norbornene changed the mechanical properties. Introduction of hydrolytically cleavable groups enabled biodegradability. Using phenyl carbamate and phenyl carbonate ester groups, we could tune the stability. Controlled release of the protein surrogate glucose oxidase was achieved over a period of 500 days. The novel preparation method presented here is a promising step toward the development of water-free injectable protein depots for controlled drug delivery.

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Section: Resultsmentioning

confidence: 99%

Injectable Anhydrous Poly(ethylene glycol) Polymer Liquids Form Protein Depot for Extended Controlled Release Applications Via Rapid In Situ Gelation

et al. 2023

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“…This is in accordance with the results found for DA hydrogels prepared with similar macromonomers. 35,53 Due to the reduced number of functional groups, the likelihood that two different functional groups find each other and react to form an elastically active chain is decreased. Furthermore, 8armPEGs with higher molecular weight consist of larger PEG chains, which are bulkier and more difficult to access than smaller ones.…”

Section: Resultsmentioning

confidence: 99%

In Situ Forming iEDDA Hydrogels with Tunable Gelation Time Release High-Molecular Weight Proteins in a Controlled Manner over an Extended Time

et al. 2021

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Off-target interactions between reactive hydrogel moieties and drug cargo as well as slow reaction kinetics and the absence of controlled protein release over an extended period of time are major drawbacks of chemically cross-linked hydrogels for biomedical applications. In this study, the inverse electron demand Diels−Alder (iEDDA) reaction between norbornene-and tetrazine-functionalized eight-armed poly(ethylene glycol) (PEG) macromonomers was used to overcome these obstacles. Oscillatory shear experiments revealed that the gel point of a 15% (w/v) eight-armed PEG hydrogel with a molecular weight of 10 kDa was less than 15 s, suggesting the potential for fast in situ gelation. However, the high-speed reaction kinetics result in a risk of premature gel formation that complicates the injection process. Therefore, we investigated the effect of polymer concentration, temperature, and chemical structure on the gelation time. The cross-linking reaction was further characterized regarding bioorthogonality. Only 11% of the model protein lysozyme was found to be PEGylated by the iEDDA reaction, whereas 51% interacted with the classical Diels−Alder reaction. After determination of the mesh size, fluorescein isothiocyanate−dextran was used to examine the release behavior of the hydrogels. When glucose oxidase was embedded into 15% (w/v) hydrogels, a controlled release over more than 250 days was achieved. Overall, the PEG-based hydrogels cross-linked via the fast iEDDA reaction represent a promising material for the long-term administration of biologics.

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“…[6,7] However, the DA reaction is not ideal for in situ gelation due to its slow reaction kinetics. [8][9][10] Further examples of biodegradable materials are systems cross-linked via Schiff base reactions such as imines and their derivatives including hydrazones and oximes. [11,12] Unfortunately, the hydrogel formation via Schiff base reactions poses a high risk for off-target reactions with cargo or molecules at the injection site by reactive groups, such as ketones and aldehydes.…”

Section: Introductionmentioning

confidence: 99%

Investigation of the Impact of Hydrolytically Cleavable Groups on the Stability of Poly(ethylene glycol) Based Hydrogels Cross‐Linked via the Inverse Electron Demand Diels–Alder (iEDDA) Reaction

Ziegler

Graf

Nagaoka

et al. 2022

Macromolecular Bioscience

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Eight-armed poly(ethylene glycol) (PEG) hydrogels cross-linked via inverse electron demand Diels-Alder reaction between norbornene and tetrazine groups are promising materials for long-term protein delivery. While a controlled release over 265 days is achieved for 15% w/v hydrogels in the previous study, the material shows high stability over 500 days despite having cleavable ester linkages between the PEG macromonomers and their functionalities. In this study, the hydrolyzable ester linkers in the PEG-norbornene precursor structure are exchanged to reduce the degradation time. To this end, 3,6-epoxy-1,2,3,6-tetrahydrophthalimide, phenyl carbamate, carbonate ester, and phenyl carbonate ester are introduced as degradable functional groups. Oscillatory shear experiments reveal that they are not affected the in situ gelation. All hydrogel types have gel points of less than 20 s even at a low polymer concentration of 5% w/v. Hydrogels with varying polymer concentrations have similar mesh sizes, all of which fell in the range of 4-12 nm. The inclusion of phenyl carbonate ester accelerates degradation considerably, with complete dissolution of 15% w/v hydrogels after 302 days of incubation in phosphate buffer (pH 7.4). Controlled release of 150 kDa fluorescein isothiocyanate-dextran over a period of at least 150 days is achieved with 15% w/v hydrogels.

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A novel anhydrous preparation of PEG hydrogels enables high drug loading with biologics for controlled release applications

Cited by 10 publications

References 39 publications

Injectable Anhydrous Poly(ethylene glycol) Polymer Liquids Form Protein Depot for Extended Controlled Release Applications Via Rapid In Situ Gelation

Injectable Anhydrous Poly(ethylene glycol) Polymer Liquids Form Protein Depot for Extended Controlled Release Applications Via Rapid In Situ Gelation

In Situ Forming iEDDA Hydrogels with Tunable Gelation Time Release High-Molecular Weight Proteins in a Controlled Manner over an Extended Time

Investigation of the Impact of Hydrolytically Cleavable Groups on the Stability of Poly(ethylene glycol) Based Hydrogels Cross‐Linked via the Inverse Electron Demand Diels–Alder (iEDDA) Reaction

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