Controlled release of anti-inflammatory peptides from reducible thermosensitive nanoparticles suppresses cartilage inflammation

Abstract

Characterized by pain, cartilage degradation, and inflammation, osteoarthritis is often treated with anti-inflammatory therapies that provide short-term relief but can have adverse side effects; intra-articular drug delivery systems with controlled release of anti-inflammatory peptides using degradable poly(N-isopropylacrylamide) (pNIPAM) nanoparticles could prolong relief and minimize these side effects. Nanoparticles provide a biocompatible drug carrier that can protect encapsulated therapeutics from enzymatic degradation and increase payload delivery upon encountering a degradation stimulus. Here we demonstrate passive targeting of inflamed cartilage ex vivo by uptake of PEGylated pNIPAM nanoparticles with degradable disulfide crosslinks (abbreviated as NGPEGSS) into chondrocytes and subsequent intracellular release of an anti-inflammatory peptide KAFAKLAARLYRKALARQLGVAA (KAFAK). The KAFAK-loaded NGPEGSS treatment reduced ex vivo inflammation to a greater extent compared to its non-degradable counterparts. This study highlights a nanoparticle system that delivers therapeutics intracellularly with improved efficacy by triggered degradation and suppresses inflammation in multiple cell types within an inflamed joint.

<p>An anti-inflammatory peptide and brain-derived neurotrophic factor-modified hyaluronan-methylcellulose hydrogel promotes nerve regeneration in rats with spinal cord injury</p>

“…Therefore, anti-inflammatory peptides and proteins have recently been exploited as alternative therapies for treatment of inflammatory conditions. 35 In light of these findings, we utilized KAFAK as an anti-inflammatory agent following traumatic injury to the spinal cord. The anti-inflammatory peptide KAFAK has the capacity to decrease the synthesis of proinflammatory cytokines by suppressing MK2, which regulates the synthesis of several proinflammatory cytokines including TNF-α, IL-1, and IL-6.…”

Advanced nanomedicines for the treatment of inflammatory diseases

“…Then, the same authors developed a more complex delivery system, based on poly (NIPAM) nanoparticles with degradable disulfide crosslinks (abbreviated as NGPEGSS), loaded with KAFAK peptides. The system relies on the co-polymerization of NIPAM and AMPS monomers, coated with polyethylene glycol (PEG) and using the degradable crosslinker bis (acryloyl)cystamine (BAC) for more effective release into the intracellular compartment [80,81]. Ex vivo, a preferential accumulation of the NPs was observed throughout the inflamed aggrecan-depleted cartilage explants compared to their healthy counterparts and, simultaneously, a significant reduction of IL-6 pro-inflammatory cytokine was measured.…”

“…Moreover, these NPs were stable and released less than 10% of the loaded KAFAK over 96h at pH=7.4 in a non-reducing environment. Thus, their ability to diffuse into the damaged cartilage, maintaining the majority of their payload prior to cell uptake by chondrocytes and macrophages, combined with a release of the peptide into these cells, represented an improvement comparatively to the treatment with the free peptide or with the previously described poly(NIPAM-co-AMPS) NPs [81].…”

Thermoresponsive Elastin-b-Collagen-Like Peptide Bioconjugate Nanovesicles for Targeted Drug Delivery to Collagen-Containing Matrices

“…Examples include: chitosan-, 151–153 poly(propylene)-, 154 PLGA-, 155, 156 poly-beta amino esters (PBAEs)-, 157 PNIPAM-, 158 and polysebacic anhydride-based 159 nanoparticles as well as HA-coated nanoparticles, 160, 161 which have been utilized to improve outcomes ranging from the enhancing the tissue engineering of cartilage to modifying osteoarthritic disease. Additionally, both ELPs and CLPs have been successfully utilized, separately, as scaffold/templates for articular cartilage regeneration, 162–166 further confirming their biocompatibility.…”