Graphene-incorporated hyaluronic acid-based hydrogel as a controlled Senexin A delivery system

doi:10.12336/biomatertransl.2022.02.007

Biomaterials Translational ›› 2022, Vol. 3 ›› Issue (2): 152-161.doi: 10.12336/biomatertransl.2022.02.007

• RESEARCH ARTICLE • Previous Articles Next Articles

Graphene-incorporated hyaluronic acid-based hydrogel as a controlled Senexin A delivery system

Panita Maturavongsadit¹, Weiwei Wu², Jingyu Fan¹, Igor B. Roninson³, Taixing Cui²^,^*(), Qian Wang¹^,^*()

1 Department of Chemistry and Biochemistry, University of South Carolina, Columbia, SC, USA
2 Department of Cell Biology and Anatomy School of Medicine Columbia, University of South Carolina, Columbia, SC, USA
3 Department of Drug Discovery & Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, SC, USA

Received:2022-04-11 Revised:2022-05-16 Accepted:2022-05-30 Online:2022-06-28 Published:2022-06-28
Contact: Taixing Cui,Qian Wang E-mail:Taixing.Cui@uscmed.sc.edu;wang263@mailbox.sc.edu
About author:Qian Wang, wang263@mailbox.sc.edu.
Taixing Cui, Taixing.Cui@uscmed.sc.edu;

Abstract

Abstract:

Perivascular delivery of therapeutic agents against established aetiologies for occlusive vascular remodelling has great therapeutic potential for vein graft failure. However, none of the perivascular drug delivery systems tested experimentally have been translated into clinical practice. In this study, we established a novel strategy to locally and sustainably deliver the cyclin-dependent kinase 8/19 inhibitor Senexin A (SenA), an emerging drug candidate to treat occlusive vascular disease, using graphene oxide-hybridised hyaluronic acid-based hydrogels. We demonstrated an approach to accommodate SenA in hyaluronic acid-based hydrogels through utilising graphene oxide nanosheets allowing for non-covalent interaction with SenA. The resulting hydrogels produced sustained delivery of SenA over 21 days with tunable release kinetics. In vitro assays also demonstrated that the hydrogels were biocompatible. This novel graphene oxide-incorporated hyaluronic acid hydrogel offers an optimistic outlook as a perivascular drug delivery system for treating occlusive vascular diseases, such as vein graft failure.

Key words: controlled drug delivery, graphene oxide, hyaluronic acid-based hydrogel, Senexin A

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Figures/Tables 12

Figure 1. (A) Schematic illustrating the synthesis of Senexin A-loaded graphene (GO-SenA) hyaluronic acid (HA)-based hydrogels via Michael addition reaction. (B) GO-SenA was first prepared and then in-situ encapsulated to form a GO-SenA-incorporated HA-based hydrogel. RT: room temperature.

Figure 2. Characterisation of the synthesised GO. (A) Scanning electron microscopic image of the synthesised GO after sonication for 1 hour. Scale bar: 4 μm. (B) Fourier transform infrared spectroscopic spectrum of the synthesised GO. (C) Physical appearances of graphene and the synthesised GO dispersed in phosphate-buffered saline. (D) Physical appearances of graphene and the synthesised GO after drying. GO: graphene oxide nanosheet; Gr: graphene flakes.

Figure 3. Preparation and characterisation of GO-SenA. (A) Fourier transform infrared spectra of GO, SenA, and GO-SenA. (B) Ultraviolet-visible spectra of GO, SenA, and GO-SenA. (C) Loading efficiency of SenA onto GO at different weight ratios (n = 3). A.U.: absorbance unit; GO: graphene oxide nanosheet; GO-SenA: Senexin A-loaded graphene oxide nanosheet; SenA: Senexin A.

Table 1. Gelation times of different GO-SenA loaded HA hydrogels which were determined by the tilting method

Formulation	MeHA (%w/v)	0.5 M DTT-Crosslinker (μL/100 μL)	GO-SenA (1:3) (%w/v)	Gelation time (min)
1	3	2	0.1	35-48
2	3	2	0.3	50-96
3	3	4	0.1	30-35
4	3	4	0.3	40-50
5	3	6	0.1	8-12
6	3	6	0.3	6-10

Figure 4. Mechanical properties of the optimised GO-SenA-loaded HA hydrogels immediately after gelation, and 3 days after gelation. The values are expressed as mean ± SD (n = 3). GO: graphene oxide nanosheet; HA: hyaluronic acid; SenA: Senexin A.

Figure 5. In vitro SenA release profiles of GO-SenA-loaded HA hydrogels. (A) In vitro SenA release profiles of GO-SenA HA hydrogels compared to SenA loaded HA hydrogels over the first 5 hours of incubation in phosphate-buffered saline at 37°C. (B) In vitro SenA release profiles of GO-SenA HA hydrogels and SenA loaded HA hydrogels over 5 days in phosphate-buffered saline at 37°C. (C) In vitro cumulative release profile of SenA from GO-SenA HA and SenA-loaded HA hydrogels calculated from B. SenA concentration loaded into both GO-SenA HA and SenA-loaded HA hydrogels were equal at 10 µmol per hydrogel. (D) In vitro SenA release profiles of GO-SenA HA hydrogels using different loading ratios of GO:SenA (1:3, 1:1, and 4:1). (E) In vitro SenA release profiles of GO-SenA HA hydrogels using 4:1 loading ratio of GO:SenA. (F) The cumulative release profile of SenA from GO-SenA HA hydrogels shown in E. All values are expressed as mean ± SD (n = 3). GO: graphene oxide nanosheet; HA: hyaluronic acid; SenA: Senexin A.

Figure 6. In vitro cytocompatibility of GO-SenA-loaded HA hydrogels. (A) Cell viability of vascular smooth muscle cells after culturing in primary medium with GO-HA hydrogels or GO-SenA-loaded HA hydrogels or without any hydrogel for 24 hours using CellTiter-Blue assay. The data were normalised to the cell viability intensity of cell alone (positive control). The values expressed are mean ± SD (n= 3) from two repeated experiments. GO: graphene oxide nanosheet; HA: hyaluronic acid; SenA: Senexin A.

Additional Figure 1. The formation and physical appearances of rigid graphene scaffold. (A) The formation of reduced GO hydrogels when using high DTT, 6 µL/100 µL. (B, C) Physical appearances of Senexin A-loaded graphene HA hydrogels immediately after gelling (D, E) Physical appearances of Senexin A-loaded graphene HA hydrogels after gelling for 3 days. DTT: dithiothreitol; GO: graphene oxide nanosheet; HA: hyaluronic acid.

Additional Figure 2. (A, B) The attachment of Senexin A-loaded graphene HA hydrogels to the decellularised scaffolds in phosphate-buffered saline immediately after gelling (A) and 1 day later (B). GO: graphene oxide nanosheet; HA: hyaluronic acid.

Additional Figure 3. (A, B) Fitting of the data for SenA release from the SenA-loaded HA hydrogels (SenA-HA) and GO-SenA HA hydrogels having different loading ratios of GO:SenA (1:3, 1:1, and 4:1) into phosphate-buffered saline (pH 7.4) to the zero order (A) and first order kinetics (B). GO: graphene oxide nanosheet; HA: hyaluronic acid; SenA: Senexin A.

Additional Table 1. Screening gelation times of HA-based hydrogels without SenA and GO incorporation

Formulation	MeHA (% w/v)	0.5 M DTT- Crosslinker (μL/100 μL)	Gelation time (min)	Gelation time (min)
1	3	2	60–70	35–48
2	3	2.8	40–45	50–96
3	3	3.4	30–35	30–35
4	4	2.8	10–15	40–50
5	4	3.7	10–15
6	4	4.6	5–7
7	5	3.4	3–5
8	5	4.6	3–4	8–12
9	5	5.7	2–3	6–10

Additional Table 2. Correlation coefficient (R2), rate constant (K), and release exponent (n) values obtained by fitting the data of the release of SenA from different hydrogel formulations into phosphate-buffered saline at pH 7.4

Formulation	Zero order		First order		Higuchi		Korsmeyer-Peppas
Formulation	K₀	R²	K₁	R²	K_h	R²	n	R²
SenA-HA	1.322	0.509	0.389	0.987	0.116	0.787	0.546	0.943
GO-SenA-HA (1:3)	1.435	0.557	0.240	0.972	0.121	0.817	0.276	0.946
GO-SenA-HA (1:1)	1.504	0.649	0.237	0.985	0.122	0.884	0.368	0.950
GO-SenA-HA (4:1)	1.572	0.762	0.228	0.949	0.122	0.938	0.545	0.905

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Graphene-incorporated hyaluronic acid-based hydrogel as a controlled Senexin A delivery system

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