Aggrecan-Mimetic, Glycosaminoglycan-Containing Nanoparticles for Growth Factor Stabilization and Delivery

Abstract

The direct delivery of growth factors to sites of tissue healing is complicated by their relative instability. In many tissues, the glycosaminoglycan (GAG) side chains of proteoglycans like aggrecan stabilize growth factors in the pericellular and extracellular space, creating a local reservoir that can be accessed during a wound healing response. GAGs also regulate growth factor-receptor interactions at the cell surface. Here we report the development of nanoparticles for growth factor delivery that mimic the size, GAG composition, and growth factor binding and stabilization of aggrecan. The aggrecan-mimetic nanoparticles are easy to assemble, and their structure and composition can be readily tuned to alter their physical and biological properties. We use basic fibroblast growth factor (FGF-2) as a model heparin-binding growth factor, demonstrating that aggrecan-mimetic nanoparticles can preserve its activity for more than three weeks. We evaluate FGF-2 activity by measuring both the proliferation and metabolic activity of bone marrow stromal cells to demonstrate that chondroitin sulfate-based aggrecan mimics are as effective as aggrecan, and heparin-based aggrecan mimics are superior to aggrecan as delivery vehicles for FGF-2.

Glycosaminoglycan and Proteoglycan Biotherapeutics in Articular Cartilage Protection and Repair Strategies: Novel Approaches to Visco‐supplementation in Orthobiologics

“…[97] In a meniscectomy model of OA in sheep, lubricin levels are significantly downregulated. [117][118][119] Figure 9. [99] The above studies show a direct inter-relationship between lubricin, boundary lubrication, and cell survival suggesting that supplementation of synovial fluid or a visco-supplement with HA and lubricin could prevent further cartilage deterioration in OA and provide conditions conducive to intrinsic cartilage repair.…”

“…PGs in the PCM and ECM thus provide a stabilized local growth factor reservoir that can be accessed by the resident cells to undertake www.advancedsciencenews.com www.advtherap.com [146,147] II Contains LDL-like receptor [145] III RGDS containing domain [143] IV Immunoglobulin repeats Bioactive, domain IV peptides [148,165,166] V Endorepellin anti angiogenic protein, 85 kDa domain V fragment [144,167,168] Therapeutic applications of recombinant domains of perlecan V i. Domain V-silk biomaterial modulates endothelial cell-platelet interaction ii. [117] CS bioscaffolds have also been developed which provide instructive cues to progenitor cells and have been applied in a number of tissue repair applications, reviewed in refs. Inhibition of amyloid-β activation of α2β1 Integrin-mediated neurotoxicity iv.…”

“…Interestingly, the collagen mimetic peptide provided superior results in cartilage repair than the fibronectin peptide. [117] Cellulose based-CS mimetic scaffolds also display positive traits in cultures of MSCs in articular cartilage repair. [228] HA derivatized with CS (or heparin) using hydrazide bifunctional reagents and reductive amination [229] is a highly flexible methodology in terms of the density of CS (or heparin) which can be achieved and is also suitable for the generation of nanoparticles.…”

Biocompatibility and Stability of Polysaccharide Polyelectrolyte Complexes Aimed at Respiratory Delivery

“…These polysaccharides have been reported to assemble into nanoparticles by a mild method of polyelectrolyte complexation [10,11], where the positively-charged amino groups of CS interact with the negatively-charged sulfate and carboxylate groups of CHS [1]. As a matter of fact, CS/CHS nanoparticles were reported in several works with varied applications, mainly including tissue engineering [12,13,14,15,16]. Other applications like cancer therapy [17,18], anticoagulant activity [10], anti-leishmanial activity [19] and cell transfection [20] were also referred.…”

Chondroitin-based nanoplexes as peptide delivery systems – Investigations into the self-assembly process, solid-state and extended release characteristics

“…Due to its acidic nature CHON is able to produce ionic complexes with 121 positively charged molecules. Indeed, similarly to HA, CHON has been shown to form 122 polyelectrolyte complexes with chitosan (Denuziere et al, 1996, Place et al, 2014, 123 trimethylchitosan (Place et al, 2014), lysozyme (van Damme et al, 1994) and polyethylenimine 124 (Pathak et al, 2009). 125…”