Dataset Information

Synthetic Studies on the Incorporation of N-Acetylallosamine in Hyaluronic Acid-Inspired Thiodisaccharides.

ABSTRACT: Two approaches for the synthesis of the thiodisaccharide ?-S-GlcA(1?3)?-S-AllNAc are described here. The target disaccharide was a C-3 epimer and thio-analogue of the hyaluronic acid repetitive unit, tuned with a thiopropargyl anomeric group for further click conjugation. Thus, we analysed and tested two convenient sequences, combining the two key steps required to introduce the thioglycosidic bonds and consequently reach the target molecule: the S_N2 substitution of a good leaving group (triflate) present at C-3 of a GlcNAc derivative and the introduction of the anomeric thiopropargyl substituent. The use of a 2-azido precursor showed to be a convenient substrate for the S_N2 step. Nevertheless, further protecting group manipulation and the introduction of the thiopropargyl anomeric residue were then required. This approach showed to provide access to a variety of thiodisaccharide derivatives as interesting building blocks for the construction of neoglycoconjugates.

SUBMITTER: Cristofalo AE

PROVIDER: S-EPMC7796257 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Synthetic Studies on the Incorporation of <i>N</i>-Acetylallosamine in Hyaluronic Acid-Inspired Thiodisaccharides.

Cristófalo Alejandro E AE Uhrig María Laura ML

Molecules (Basel, Switzerland) 20210101 1

Two approaches for the synthesis of the thiodisaccharide β-S-GlcA(1→3)β-S-AllNAc are described here. The target disaccharide was a C-3 epimer and thio-analogue of the hyaluronic acid repetitive unit, tuned with a thiopropargyl anomeric group for further click conjugation. Thus, we analysed and tested two convenient sequences, combining the two key steps required to introduce the thioglycosidic bonds and consequently reach the target molecule: the S<sub>N</sub>2 substitution of a good leaving gro ...[more]

PMID: 33401465

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Project description:Cell-loaded hydrogels are frequently applied in cartilage tissue engineering for their biocompatibility, ease of application, and ability to conform to various defect sites. As a bioactive adjunct to the biomaterial, transforming growth factor beta (TGF-β) has been shown to be essential for cell differentiation into a chondrocyte phenotype and maintenance thereof, but the low amounts of endogenous TGF-β in the in vivo joint microenvironment necessitate a mechanism for controlled delivery and release of this growth factor. In this study, TGF-β3 was directly loaded with human bone marrow-derived mesenchymal stem cells (MSCs) into poly-d,l-lactic acid/polyethylene glycol/poly-d,l-lactic acid (PDLLA-PEG) hydrogel, or PDLLA-PEG with the addition of hyaluronic acid (PDLLA/HA), and cultured in vitro. We hypothesize that the inclusion of HA within PDLLA-PEG would result in a controlled release of the loaded TGF-β3 and lead to a robust cartilage formation without the use of TGF-β3 in the culture medium. ELISA analysis showed that TGF-β3 release was effectively slowed by HA incorporation, and retention of TGF-β3 in the PDLLA/HA scaffold was detected by immunohistochemistry for up to 3 weeks. By means of both in vitro culture and in vivo implantation, we found that sulfated glycosaminoglycan production was higher in PDLLA/HA groups with homogenous distribution throughout the scaffold than PDLLA groups. Finally, with an optimal loading of TGF-β3 at 10 μg/mL, as determined by RT-PCR and glycosaminoglycan production, an almost twofold increase in Young's modulus of the construct was seen over a 4-week period compared to TGF-β3 delivery in the culture medium. Taken together, our results indicate that the direct loading of TGF-β3 and stem cells in PDLLA/HA has the potential to be a one-step point-of-care treatment for cartilage injury. STATEMENT OF SIGNIFICANCE: Stem cell-seeded hydrogels are commonly used in cell-based cartilage tissue engineering, but they generally fail to possess physiologically relevant mechanical properties suitable for loading. Moreover, degradation of the hydrogel in vivo with time further decreases mechanical suitability of the hydrogel due in part to the lack of TGF-β3 signaling. In this study, we demonstrated that incorporation of hyaluronic acid (HA) into a physiologically stiff PDLLA-PEG hydrogel allowed for slow release of one-time preloaded TGF-β3, and when loaded with adult mesenchymal stem cells and cultured in vitro, it resulted in higher chondrogenic gene expression and constructs of significantly higher mechanical strength than constructs cultured in conventional TGF-β3-supplemented medium. Similar effects were also observed in constructs implanted in vivo. Our results indicate that direct loading of TGF-β3 combined with HA in the physiologically stiff PDLLA-PEG hydrogel has the potential to be used for one-step point-of-care treatment of cartilage injury.

Dataset Information

Synthetic Studies on the Incorporation of N-Acetylallosamine in Hyaluronic Acid-Inspired Thiodisaccharides.

Publications

Synthetic Studies on the Incorporation of <i>N</i>-Acetylallosamine in Hyaluronic Acid-Inspired Thiodisaccharides.

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