Bioresponsive Cytokine Delivery Responding to Matrix Metalloproteinases.

Cytokines are regulated in acute and chronic inflammation, including rheumatoid arthritis (RA) and myocardial infarction (MI). However, the dynamic windows within which cytokine activity/inhibition is desirable in RA and MI change timely and locally during the disease. Therefore, traditional, static delivery regimens are unlikely to meet the idiosyncrasy of these highly dynamic pathophysiological and individual processes. Responsive delivery systems and biomaterials, sensing surrogate markers of inflammation (i.e., matrix metalloproteinases - MMPs) and answering with drug release, may present drug activity at the right time, manner, and place. This article discusses MMPs as surrogate markers for disease activity in RA and MI to clock drug discharge to MMP concentration profiles from MMP-responsive drug delivery systems and biomaterials.

Targeting interleukin-4 to the arthritic joint.

Anti-inflammatory cytokines are a promising class of therapeutics for treatment of rheumatoid arthritis (RA), but their use is currently limited by a rapid clearance and systemic toxicity. Interleukin-4 is a small cytokine with potential for RA therapy. To increase its pharmacokinetic features, we engineered a murine IL4 conjugate by incorporating an unnatural amino acid through genetic code expansion to which PEG-folate, as a targeting moiety and PEG alone as control, were site-specifically bound. Both IL4 conjugates retained bioactivity and induced primary murine macrophage polarization into an alternatively activated (M2) related phenotype. The PEGylated conjugates had a terminal half-life of about four hours in healthy mice compared to unPEGylated IL4 (0.76 h). We showed that both conjugates successfully accumulated into arthritic joints in an antigen-induced arthritis (AIA) mouse model, as assessed by non-invasive fluorescence imaging. The modular nature of the IL4 conjugate chemistry presented herein facilitates easy adaption of PEG chain length and targeting moieties for further improvement of half-life and targeting function for future efficacy studies.