Hyaluronic acid-coated gold nanorods enhancing BMP-2 peptide delivery for chondrogenesis

Abstract

Bone morphogenic protein-2 (BMP-2) knuckle epitope peptide has been recently discovered and known to activate chondrogenesis. However, the applications of this soluble peptide remain very limited due to rapid diffusion resulting in poor cellular uptake into target cells. We herein designed nanoparticles made from hyaluronic acid functionalized gold nanorods (GNRs) to conjugate with thiolated BMP-2 knuckle epitope peptide via a two-step reaction. Hyaluronic acid was modified to have thiol functional groups to replace the cetyl trimethylammonium bromide ligands on the surface of GNRs. The thiolated peptides were subsequently reacted with hyaluronic acid on the surface on GNRs via a maleimide-hydrazide crosslinker. The conjugation was confirmed by the change of surface charge of GNRs and the plasmon shift. A colorimetric peptide assay suggested more than 69% of the thiolated peptides were conjugated with the hyaluronic acid coated gold nanorods. Moreover, in vitro cell viability showed that BMP-2 conjugated hyaluronic acid functionalized gold nanorods (B2HGR) were cytocompatible and did not cause cytotoxicity to fibroblast cells. The B2HGRs also significantly promote cellular uptake of the BMP-2 peptides in both human mesenchymal stem cells and porcine chondrocytes due to multivalent ligand binding to the BMP receptors on the cell surface resulting in receptor-mediated endocytosis. The enhanced cellular uptake was clearly observed under a confocal microscope resulting in the significant activation of type II collagen gene expression and glucosaminoglycan secretion in those cells. Furthermore, our delivery system is a proof-of-concept of using scaffolds in combination with nanodelivery platform to enhance cartilaginous repair. The peptide loading capacity and the release is not limited by the scaffolds. Therefore, our delivery platform has potential applications for cartilage regeneration in a preclinical and clinical setting in the future.

The application prospect of metal/metal oxide nanoparticles in the treatment of osteoarthritis

“…For example, using liposomes to enclose gold NPs absorbed with fish oil, which increase the stability (Sarkar et al 2019 ). On the other hand, a growing number of drugs are being transported using gold NPs for their good biocompatibility and drug binding ability, such as hyaluronic acid, chondroitin sulfate, 2-[(aminocarbonyl)amino]-5-(4-fluorophenyl)-3-thiophenecarboxamide (TPCA-1), and rutin (Dwivedi et al 2015 , Sansanaphongpricha et al 2020 , Gul et al 2018 , Wang et al 2020 ).…”

Gold Nanomaterials and Bone/Cartilage Tissue Engineering: Biomedical Applications and Molecular Mechanisms

“…The proliferation and differentiation of BMSCs can be considered as independent programmable processes, and controlling these processes in a predictable manner is crucial to regeneration of the desired tissue type. It has been reported that gold nanomaterials, mainly AuNPs, promoted osteogenic and chondrogenic differentiation through their effects on BMSCs (Yi et al, 2010;Sansanaphongpricha et al, 2020). The molecular mechanism mainly involved mitogen-activated protein kinase (MAPK), Wnt/β-catenin, and autophagy.…”

“…As for AuNRs, it is also easy to modify the surface of their surface. And with the help of other drugs or protein, AuNRs have been shown to promote chondrogenesis (Sansanaphongpricha et al, 2020). As can be seen from the examples above, gold nanomaterials are not only useful as therapeutic agents for cartilage disease but also have enormous potential in cartilage TE.…”

“…Certainly, the function of above molecules was enhanced by the carriers. Similarly, AuNRs could serve as delivery carries of BMP-2 and siRNA and ultimately promote osteogenesis and chondrogenesis (Tsai et al, 2007;Zhao et al, 2015;Sansanaphongpricha et al, 2020). In summary, there is massive clinical potential for gold nanomaterials as carrier in bone and cartilage TE.…”

Effect of BMP-2 Adherent to Resorbable Sutures on Cartilage Repair: A Rat Model of Xyphoid Process

“…Three days after surgery, the anastomoses with IGF-I coated sutures showed better anastomotic healing (histology appearance) and greater capacity to withstand biomechanical stress (busting pressure) than the control groups [ 23 ]. As an FDA-approved biologic, BMP-2 appears promising in promoting chondrogenesis and cartilage repair at pre-clinical setting [ 27 , 28 , 29 ]. The current study with BMP-2 coating on the resorbable sutures provides evidence to further support the theory that growth factors can be successfully introduced to a local tissue environment by coating suture material.…”