Synthetic nanoscale electrostatic particles as growth factor carriers for cartilage repair

Abstract

The efficient transport of biological therapeutic materials to target tissues within the body is critical to their efficacy. In cartilage tissue, the lack of blood vessels prevents the entry of systemically administered drugs at therapeutic levels. Within the articulating joint complex, the dense and highly charged extracellular matrix (ECM) hinders the transport of locally administered therapeutic molecules. Consequently, cartilage injury is difficult to treat and frequently results in debilitating osteoarthritis. Here we show a generalizable approach in which the electrostatic assembly of synthetic polypeptides and a protein, insulin‐like growth factor‐1 (IGF‐1), can be used as an early interventional therapy to treat injury to the cartilage. We demonstrated that poly(glutamic acid) and poly(arginine) associated with the IGF‐1 via electrostatic interactions, forming a net charged nanoscale polyelectrolyte complex (nanoplex). We observed that the nanoplex diffused into cartilage plugs in vitro and stimulated ECM production. In vivo, we monitored the transport, retention and therapeutic efficacy of the nanoplex in an established rat model of cartilage injury. A single therapeutic dose, when administered within 48 hr of the injury, conferred protection against cartilage degradation and controlled interleukin‐1 mediated inflammation. IGF‐1 contained in the nanoplex was detected in the joint space for up to 4 weeks following administration and retained bioactivity. The results indicate the potential of this approach as an early intervention therapy following joint injury to delay or even entirely prevent the onset of osteoarthritis.

Cartilage-penetrating nanocarriers improve delivery and efficacy of growth factor treatment of osteoarthritis

“…There is tremendous unmet medical need for a disease-modifying OA drug. Anabolic growth factors, such as bone morphogenetic protein 7, fibroblast growth factor 18 (FGF-18), and IGF-1, have shown potential for disease modification by decreasing chondrocyte loss and increasing matrix production in preclinical studies (12,24,(38)(39)(40). Anabolic disease-modifying strategies are particularly interesting in light of a recent finding by Heinemeier et al (41) that revealed that cartilage renewal in adults is driven by aggrecan proteoglycan synthesis, with the underlying collagen matrix exhibiting no renewal in both healthy and osteoarthritic joints (41).…”

“…Tunable surface charge is another key feature of the partially PEGylated dendrimer-drug conjugate system. Previous work in our groups has shown that positively charged nanocarriers bind and penetrate cartilage efficiently via reversible electrostatic interactions with anionic cartilage matrix proteoglycans (11,12,15). Yet, the effects of degree of charge on these delivery properties have not been thoroughly explored.…”

Targeting the extracellular matrix for delivery of bioactive molecules to sites of arthritis

“…Nanoplexes of alternating layers of anionic poly (glutamic acid) and cationic poly (arginine) were readily able to penetrate cartilage, and IGF‐1 from loaded nanoplexes was detected in the synovium 4 weeks after intra‐articular injection compared to 9 days for free IGF‐1. IGF‐1 nanoplexes ensured cartilage integrity was retained in a rat model of cartilage injury, and synovial IL‐1β levels were significantly reduced in the nanoplex‐treated animals (Shah et al, ). Cartilage can also be readily penetrated by the strongly basic protein avidin due to its electrostatic attraction to negatively charged glycosaminoglycans (GAGs).…”

Cyclodextrin Cationic Polymer-Based Nanoassemblies to Manage Inflammation by Intra-Articular Delivery Strategies

“…However, sustained intra-articular delivery strategies by means of drug conjugated or entrapped in hydrogels have some limitations such as (i) the chemical modification could inactivate the drug and (ii) the delayed release of a small drug is generally achieved by increasing the crosslinking of the polymer, which could not flow through a syringe and finally not match the mechanical features of the joint [ 6 ]. To contrast the short therapeutic time, decreasing the frequency of administration, thus optimizing the cartilage penetration, more injectable nanoformulations based on cationic polyelectrolyte needed to be proposed for intra-articular delivery [ 7 ].…”