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Mild and Efficient Strategy for Site-Selective Aldehyde Modification of Glycosaminoglycans: Tailoring Hydrogels with Tunable Release of Growth Factor
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
2013 (English)In: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 14, no 7, 2427-2432 p.Article in journal (Refereed) Published
Abstract [en]

Aldehydes have been used as an important bioorthogonal chemical reporter for conjugation of large polymers and bioactive substances. However, generating aldehyde functionality on carbohydrate-based biopolymers without changing its native chemical structure has always persisted as a challenging task. The common methods employed to achieve this require harsh reaction conditions, which often compromise the structural integrity and biological function of these sensitive molecules. Here we report a mild and simple method to graft aldehydes groups on glycosaminoglycans (GAGs) in a site-selective manner without compromising the structural integrity of the biopolymer. This regio-selective modification was achieved by conjugating the amino-glycerol moiety on the carboxylate residue of the polymer, which allowed selective cleavage of pendent diol groups without interfering with the C2C3 diol groups of the native glucopyranose residue. Kinetic evaluation of this reaction demonstrated significant differences in second-order reaction rate for periodate oxidation (by four-orders of magnitude) between the two types of vicinal diols. We employed this chemistry to develop aldehyde modifications of sulfated and nonsulfated GAGs such as hyaluronic acid (HA), heparin (HP), and chondroitin sulfate (CS). We further utilized these aldehyde grafted GAGs to tailor extracellular matrix mimetic injectable hydrogels and evaluated its rheological properties. The composition of the hydrogels was also found to modulate release of therapeutic protein such as FGF-2, demonstrating controlled release (60%) for over 14 days. In short, our result clearly demonstrates a versatile strategy to graft aldehyde groups on sensitive biopolymers under mild conditions that could be applied for various bioconjugation and biomedical applications such as drug delivery and regenerative medicine.

Place, publisher, year, edition, pages
2013. Vol. 14, no 7, 2427-2432 p.
National Category
Natural Sciences
Identifiers
URN: urn:nbn:se:uu:diva-204978DOI: 10.1021/bm400612hISI: 000321793700035OAI: oai:DiVA.org:uu-204978DiVA: diva2:641366
Note

De två (2) första författarna delar förstaförfattarskapet.

Available from: 2013-08-16 Created: 2013-08-13 Last updated: 2017-12-06Bibliographically approved
In thesis
1. Insights into dynamic covalent chemistry for bioconjugation applications
Open this publication in new window or tab >>Insights into dynamic covalent chemistry for bioconjugation applications
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Dynamic covalent chemistry (DCC) is currently exploited in several areas of biomedical applications such as in drug discovery, sensing, molecular separation, catalysis etc. Hydrazone and oxime chemistry have several advantages, such as mild reaction conditions, selectivity, efficiency, and biocompatibility and therefore, have the potential to be for bioconjugation applications. However, these reactions suffer from major drawbacks of slow reaction rate and poor bond stability under physiological conditions. In this regard, the work presented in this thesis focuses on designing novel bioconjugation reactions amenable under physiological conditions with tunable reaction kinetics and conjugation stability.

The first part of the thesis presents different strategies of dynamic covalent reactions utilized for biomedical applications. In the next part, a detailed study related to the mechanism and catalysis of oxime chemistry was investigated in the presence of various catalysts. Aniline, carboxylate and saline were selective as target catalysts and their reaction kinetics were compared under physiological conditions (Paper I and II). Then we attempted to explore the potential of those chemistries in fabricating 3D hydrogel scaffolds for regenerative medicine application. A novel mild and regioselective method was devised to introduce an aldehyde moiety onto glycosaminoglycans structure. This involved the introduction of amino glycerol to glycosaminoglycans, followed by regioselective oxidation of tailed flexible diol without affecting the C2-C3 diol groups on the disaccharide repeating unit. The oxidation rate of the tailed flexible diol was 4-times faster than that of C2-C3 diol groups of native glycosaminoglycan. This strategy preserves the structural integrity of the glycosaminoglycans and provides a functional aldehyde moiety (Paper III). Further, different types of hydrazones were designed and their hydrolytic stability under acidic condition was carefully evaluated. The hydrazone linkage with the highest hydrolytic stability was utilized in the preparation of extracellular matrix hydrogel for delivery of bone morphogenetic proteins 2 in bone regeneration (Paper IV) and studied for controlled release of the growth factor (Paper III).

In summary, this thesis presents a selection of strategies for designing bioconjugation chemistries that possess tunable stability and reaction kinetics under physiological conditions. These chemistries are powerful tools for conjugation of biomolecules for the biomedical applications.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2017. 59 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1554
Keyword
dynamic covalent chemistry, reaction mechanism, hydrogel, bioconjugation, catalysis
National Category
Polymer Chemistry Materials Chemistry Organic Chemistry
Research subject
Chemistry with specialization in Polymer Chemistry
Identifiers
urn:nbn:se:uu:diva-329022 (URN)978-91-513-0065-8 (ISBN)
Public defence
2017-10-26, Room 10132, Ånströmlaboratoriet, Lägerhyddsvägen 1, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2017-10-03 Created: 2017-09-06 Last updated: 2017-10-18

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Wang, ShujiangOommen, Oommen P.Yan, HongjiVarghese, Oommen P.

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