Journal of Shanghai Jiao Tong University (Medical Science) >

2021 , Vol. 41 >Issue 2: 140 - 146

DOI: https://doi.org/10.3969/j.issn.1674-8115.2021.02.003

Basic research

Fabrication and characterization of matrix metalloproteinase-responsive G4 PAMAM-IBU/GelMA hydrogel

  • Chuan-dong CAI ,
  • Fei WANG ,
  • Wen-guo CUI ,
  • Cun-yi FAN ,
  • Shen LIU
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  • 1.Department of Orthopedics, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University, Shanghai 200233, China
    2.Department of Orthopedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine; Shanghai Institute of Traumatology and Orthopedics; Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai 200025, China

Received date: 2020-06-01

  Online published: 2021-02-28

Supported by

National Natural Science Foundation of China(81772314);Shanghai Municipal Education Commission—Gaofeng Clinical Medicine Grant Support(20191829)

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Abstract

Objective

·To fabricate matrix metalloproteinase (MMP)-responsive gelatin (Gel) hydrogel loaded with generation 4 polyamindoamine (G4 PAMAM)/ibuprofen (IBU) polyplexes (G4 PAMAM-IBU), and investigate its characteristics in vitro.

Methods

·The G4 PAMAM was mixed with IBU powder to form G4 PAMAM-IBU polyplexes under ultrasound vortex. The concentration of IBU in the saturated G4 PAMAM-IBU solution was determined by ultraviolet spectrophotometer. The solubilization ability of G4 PAMAM for IBU and the release of IBU in G4 PAMAM-IBU were assessed. And the ability of IBU and G4 PAMAM-IBU to inhibit the proliferation of rat fibroblasts was verified by CCK-8 assay. Meanwhile, to achieve the on-demand release of G4 PAMAM-IBU, Gel and methacrylic anhydride were used to synthesize methacrylate modified gelatin (GelMA) through an addition reaction, MMP-responsive hydrogel was formed under 365 nm light, and the G4 PAMAM-IBU polyplexes were embedded in the hydrogel. The microscopic morphology of the hydrogel was observed by scanning electron microscope (SEM) and the amount of released IBU was measured by ultraviolet spectrophotometer. Then, drug-loaded GelMA hydrogel was co-cultured with fibroblasts, and the effect of hydrogel on proliferation of fibroblasts was evaluated by CCK-8 assay and live/dead cell staining. The differences in the quantitative data among the groups were analyzed by using one-way ANOVA.

Results

·G4 PAMAM-IBU was formed successfully, the solubility of IBU in water increased obviously, and G4 PAMAM-IBU could gradually dissociate within 12 h and thereby release IBU as well. Compared with the blank control group, the concentration of IBU alone needed to reach 300 μg/mL to inhibit the proliferation of fibroblasts (P=0.023), while the concentration of IBU in G4 PAMAM-IBU was 100 μg/mL to significantly inhibit the proliferation of fibroblasts (P=0.000). The SEM images and released IBU detection results showed that the internal porosity of the prepared G4 PAMAM-IBU/GelMA hydrogel increased and the release of the drug accelerated. Besides, the in vitro results showed that compared with the IBU/GelMA hydrogel, there were less live cells and more dead cells in the G4 PAMAM-IBU/GelMA hydrogel-treated fibroblasts. G4 PAMAM-IBU/GelMA hydrogel had a greater proliferation inhibitory effect than the IBU/GelMA hydrogel. And the addition of MMP further enhanced the inhibitory effect on fibroblasts.

Conclusion

·G4 PAMAM can significantly increase the solubility of IBU and improve its drug effect; the G4 PAMAM-IBU/GelMA hydrogel has a sustained drug release behavior responding to MMP and can inhibit the proliferation of fibroblasts sustainably.

Key words： hydrogel; generation 4 polyamindoamine (G4 PAMAM); ibuprofen (IBU); peritendinous adhesion

Cite this article

Chuan-dong CAI , Fei WANG , Wen-guo CUI , Cun-yi FAN , Shen LIU . Fabrication and characterization of matrix metalloproteinase-responsive G4 PAMAM-IBU/GelMA hydrogel[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2021 , 41(2) : 140 -146 . DOI: 10.3969/j.issn.1674-8115.2021.02.003

References

1 Jaibaji M. Advances in the biology of zone Ⅱ flexor tendon healing and adhesion formation[J]. Ann Plast Surg, 2000, 45(1): 83-92.
2 James R, Kesturu G, Balian G, et al. Tendon: biology, biomechanics, repair, growth factors, and evolving treatment options[J]. J Hand Surg, 2008, 33(1): 102-112.
3 Zeng J, Xu X, Chen X, et al. Biodegradable electrospun fibers for drug delivery[J]. J Control Release, 2003, 92(3): 227-231.
4 Verreck G, Chun I, Rosenblatt J, et al. Incorporation of drugs in an amorphous state into electrospun nanofibers composed of a water-insoluble, nonbiodegradable polymer[J]. J Control Release, 2003, 92(3): 349-360.
5 Blomgran P, Blomgran R, Ernerudh J, et al. Cox-2 inhibition and the composition of inflammatory cell populations during early and mid-time tendon healing[J]. Muscles Ligaments Tendons J, 2017, 7(2): 223-229.
6 Yang DJ, Xiong CD, Govender T, et al. Preparation and drug-delivery potential of metronidazole-loaded PELA tri-block co-polymeric electrospun membranes[J]. J Biomater Sci Polym Ed, 2009, 20(9): 1321-1334.
7 Liu S, Hu C, Li F, et al. Prevention of peritendinous adhesions with electrospun ibuprofen-loaded poly(L-lactic acid)-polyethylene glycol fibrous membranes[J]. Tissue Eng Part A, 2013, 19(3-4): 529-537.
8 Irvine J, Afrose A, Islam N. Formulation and delivery strategies of ibuprofen: challenges and opportunities[J]. Drug Dev Ind Pharm, 2018, 44(2): 173-183.
9 Wan Y, Chen W, Yang J, et al. Biodegradable poly(L-lactide)-poly(ethylene glycol) multiblock copolymer: synthesis and evaluation of cell affinity[J]. Biomaterials, 2003, 24(13): 2195-2203.
10 Fan CX, Shi JJ, Zhuang Y, et al. Myocardial-infarction-responsive smart hydrogels targeting matrix metalloproteinase for on-demand growth factor delivery[J]. Adv Mater, 2019, 31(40): e1902900.
11 Loiselle AE, Bragdon GA, Jacobson JA, et al. Remodeling of murine intrasynovial tendon adhesions following injury: MMP and neotendon gene expression[J]. J Orthop Res, 2009, 27(6): 833-840.
12 程若昱, 燕宇飞, 陈皓, 等. 双效骨诱导性的有机-无机水凝胶的构建及其骨再生研究[J]. 上海交通大学学报(医学版), 2018, 38(8): 900-909.
13 Ribeiro JS, Bordini EAF, Ferreira JA, et al. Injectable MMP-responsive nanotube-modified gelatin hydrogel for dental infection ablation[J]. ACS Appl Mater Interfaces, 2020, 12(14): 16006-16017.
14 Tan V, Nourbakhsh A, Capo J, et al. Effects of nonsteroidal anti-inflammatory drugs on flexor tendon adhesion[J]. J Hand Surg Am, 2010, 35(6): 941-947.
15 Yang J, Li K, He D, et al. Toward a better understanding of metabolic and pharmacokinetic characteristics of low-solubility, low-permeability natural medicines[J]. Drug Metab Rev, 2020, 52(1): 19-43.
16 Bilia AR, Piazzini V, Risaliti L, et al. Nanocarriers: a successful tool to increase solubility, stability and optimise bioefficacy of natural constituents[J]. Curr Med Chem, 2019, 26(24): 4631-4656.
17 Li J, Liang H, Liu J, et al. Poly (amidoamine) (PAMAM) dendrimer mediated delivery of drug and pDNA/siRNA for cancer therapy[J]. Int J Pharm, 2018, 546(1-2): 215-225.
18 Geiger BC, Wang S, Padera RF Jr, et al. Cartilage-penetrating nanocarriers improve delivery and efficacy of growth factor treatment of osteoarthritis[J]. Sci Transl Med, 2018, 10(469): eaat8800.
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