Minimally invasive, sustained-release relaxin-2 microparticles reverse arthrofibrosis

Abstract

Substantial advances in biotherapeutics are distinctly lacking for musculoskeletal diseases. Musculoskeletal diseases are biomechanically complex and localized, highlighting the need for novel therapies capable of addressing these issues. All frontline treatment options for arthrofibrosis, a debilitating musculoskeletal disease, fail to treat the disease etiology—the accumulation of fibrotic tissue within the joint space. For millions of patients each year, the lack of modern and effective treatment options necessitates surgery in an attempt to regain joint range of motion (ROM) and escape prolonged pain. Human relaxin-2 (RLX), an endogenous peptide hormone with antifibrotic and antifibrogenic activity, is a promising biotherapeutic candidate for musculoskeletal fibrosis. However, RLX has previously faltered through multiple clinical programs because of pharmacokinetic barriers. Here, we describe the design and in vitro characterization of a tailored drug delivery system for the sustained release of RLX. Drug-loaded, polymeric microparticles released RLX over a multiweek time frame without altering peptide structure or bioactivity. In vivo, intraarticular administration of microparticles in rats resulted in prolonged, localized concentrations of RLX with reduced systemic drug exposure. Furthermore, a single injection of RLX-loaded microparticles restored joint ROM and architecture in an atraumatic rat model of arthrofibrosis with clinically derived end points. Finally, confirmation of RLX receptor expression, RXFP1, in multiple human tissues relevant to arthrofibrosis suggests the clinical translational potential of RLX when administered in a sustained and targeted manner.

Relaxin in fibrotic ligament diseases: Its regulatory role and mechanism

“…To improve the metabolic efficiency of the RLX-2, follow-up studies found that RLX-loaded Poly lactide coglycolide (PLGA) microparticles (MPs) could effectively exert the anti-fibrotic effect of RLX and significantly increased the duration of RLX activity. The study by Kirsch et al (2022) showed that RXFP1 was also expressed in periarticular tissue of the shoulder joint of FS patients. These results suggested RLX might represented a novel therapeutic target for the treatment of frozen shoulder.…”

“…Fibrosis was a chronic disease requiring long-term use of RLX ( Samuel et al, 2005 ; Blessing et al, 2019 ). However, the half-life of RLX is only 1.6 h, which limits its clinical application ( Kirsch et al, 2022 ). Therefore, RLX must be administered non-intravenously, usually requiring several times a day.…”

“…So, after long-term use of RLX, gradual discontinuation may be required. Although animal studies indicated that RLX was not significantly toxic to the kidney ( Blessing et al, 2019 ; Kirsch et al, 2022 ), the biological safety of RLX should be fully considered before the clinical application.…”

“…Table 1 summarizes the regulation of RLX in different organs and FLDs. In recent years, RLX has been shown to reduce the ECM formation and promote ECM degradation in a rat shoulder joint immobilization model ( Blessing et al, 2019 ; Kirsch et al, 2022 ) . However, the underlying mechanisms of RLX remain unclear, especially the major cellular, molecular and signaling pathways.…”

The diverse influences of relaxin-like peptide family on tumor progression: Potential opportunities and emerging challenges

“…It also plays a role in vascular dilation and the maintenance of sperm motility. These effects occur through the activation of relaxin-mediated signaling pathways, including the pERK-nNOS-NO-cGMP, PI3K-AKT-eNOS, cyclic adenosine monophosphate (cAMP)-protein kinase A, nuclear factor kappa B (NF-κB), peroxisome proliferator-activated receptor gamma, and vascular endothelial growth factor (VEGF) signaling pathways, as well as the inhibition of the tumor growth factor (TGF)-β1/pSmad pathway [ [13] , [14] , [15] , [16] , [17] , [18] , [19] , [20] , [21] , [22] , [23] , [24] , [25] , [26] , [27] , [28] ]. RLN3 is a neuropeptide primarily synthesized in the brain and maps to chromosome 19p13.3 [ 29 , 30 ].…”