Microparticles Locally Deliver Active Interleukin‐1 Receptor Antagonist In Vivo

Abstract

Despite significant research in therapeutic protein delivery, localized and sustained delivery of active therapeutic proteins remains a challenge. Delivery is a particular challenge for therapeutic proteins with a short half-life. Herein, localized delivery of interleukin-1 receptor antagonist (IL-1Ra) by mineral coated microparticles (MPs) is assessed in a healing rat medial collateral ligament (MCL). The local tissue concentration and systemic serum concentration of IL-1Ra, the anti-inflammatory activity of IL-1Ra delivered with MPs, and whether IL-1Ra loaded MPs (IL-1Ra MPs) are immunogenic in a healing ligament are also examined. IL-1Ra MPs significantly increase the local concentration of IL-1Ra compared to soluble IL-1Ra at 7 and 14 days after treatment but do not elevate the systemic concentration of IL-1Ra at these time points, indicating localized delivery of IL-1Ra. IL-1Ra MPs significantly reduce inflammation caused by the MPs themselves, indicating the IL-1Ra is active. Finally, IL-1Ra MPs do not induce a foreign body response and decrease the immunogenicity of human IL-1Ra in a healing rat MCL. Overall, mineral coated microparticles have the ability to locally deliver active therapeutic proteins for an extended period of time.

Single-dose mRNA therapy via biomaterial-mediated sequestration of overexpressed proteins

“…Previously, researchers have demonstrated that either 5 μg/cm 2 daily doses( 37 ) or a sustained release of 7 to 14 μg/cm 2 of bFGF from a scaffold ( 38 – 40 ) was required to improve outcomes in this murine model of diabetic wound healing and that increased bFGF dosage showed no improvement or worse outcomes ( 38 , 39 ). As we have previously demonstrated that these mineral coatings are capable of sustained delivery of a variety of growth factors ( 27 , 28 , 41 – 43 ), including bFGF ( 14 ), we selected 5 μg of sustained delivery from MCMs as an experimental condition to allow for comparison of single-dose mRNA therapy versus recombinant protein therapy.…”

“…Decreased expected time to complete closure with CM-mRNA + MCM treatment in this model indicated that MCMs offer significant increase in potential therapeutic utility of mRNA delivery. As we have previously demonstrated, the promiscuous electrostatic binding of mineral coatings allows for sustained release of a range of other growth factors, cytokines, and enzymes, including bone morphogenetic protein–2 ( 27 , 45 ), vascular endothelial growth factor ( 14 , 27 , 43 ), interleukin-1RA (IL-1RA) ( 41 ), IL-10 ( 46 ), NT-3 (neurotrophin-3) ( 42 ), and chondroitinase ABC ( 47 ). Therefore, our MCM-mediated overexpress and sequester approach may have broad potential in therapeutic applications where in situ production and retention of highly bioactive secreted proteins would be beneficial.…”

Sequential sequestrations increase the incorporation and retention of multiple growth factors in mineralized collagen scaffolds

“…In this manuscript, we described the use of modied simulated body uid (mSBF) and sequential sequestrations to incorporate BMP2 and VEGF into mineralized collagen scaffolds. This work seeks to adapt promising results using mSBF to deposit a mineral layer that can sequester growth factors onto surfaces [58][59][60][61][62][63][64] to selectively incorporate growth factors used for bone repair applications into three-dimensional, porous biomaterials. Our primary goal is to improve growth factor incorporation and retention into mineralized collagen scaffolds via sequential sequestration strategies to enhance in vivo bone healing.…”

“…Modied simulated body uid (mSBF) was made according to previous recipes. [58][59][60][61][62][63][64] Briey, 1.41 mM sodium chloride (NaCl, Sigma Aldrich), 4.0 mM potassium chloride (KCl, Sigma Aldrich), 0.5 mM magnesium sulfate (MgSO 4 , Sigma Aldrich), 1.0 mM magnesium chloride (MgCl 2 , Sigma Aldrich), 5.0 mM calcium chloride (CaCl 2 , Sigma Aldrich), 1.0 mM potassium phosphate (KH 2 PO 4 , Sigma Aldrich), and 4.2 mM sodium carbonate (NaHCO 3 , Sigma Aldrich) were dissolved in deionized water and sterile ltered through a MilliporeSigma Stericup with a 0.22 mm lter (Fisher Scientic, Hampton, New Hampshire USA). mSBF was stored at 4 C until use.…”

“…Our group has previously used strategies such as photopatterning, 50,51 covalent immobilization, [52][53][54][55] and sequestration modulated by glycosaminoglycan content 56 and small molecules 57 to add growth factors to non-mineralized and mineralized collagen scaffolds. Recently, the Murphy lab has described the use of modied simulated body uid (mSBF) to create mineral coatings on material surfaces to deliver growth factors, [58][59][60][61][62] plasmid DNA lipoplexes, 63 and condensed mRNA. 64 We were particularly interested in the work by Clements et al in which they performed sequential sequestrations to layer interleukin-1 receptor antagonist on nanoparticles to prolong in vivo activity.…”