Intra-cartilage depot delivery of electrically-charged IL-1RA for targeting osteoarthritis-associated inflammation and catabolism in multiple joint tissues

Northeastern University, Boston MA

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Abstract

Project Summary/Abstract Osteoarthritis (OA) pain remains an intractable problem with few treatment options. Centrally acting analgesic drugs carry the risk of addictive side effects. Thus, local sustained analgesic delivery is an attractive strategy for development of novel OA pain therapies. Local intra-articular (IA) delivery, however, remains inadequate due to rapid drug clearance from the synovial joint space requiring multiple injections that cause toxicity. This is further complicated by the dense and highly negatively charged cartilage matrix that prevents drugs from reaching their target sites. The parent R01 addressed this challenge by developing cartilage targeting and residing cationic anti-catabolic and pro-anabolic disease modifying OA therapeutics. For example, a receptor antagonist of IL-1 (IL-1RA) was fused with an optimally charged cationic peptide carrier (CPC-IL-1RA), and its effectiveness in suppressing OA associated catabolism was demonstrated in-vitro as well as in vivo with only a one-time dose. Here we will broaden the impact of our work in targeted drug delivery to treatment of OA pain by evaluating the effectiveness in sustained release formulations of (i) cationic fusion CPC-IL-1RA (already developed as part of the parent R01 tasks) and (ii) cationic CCR2 receptor antagonist (CCR2RA). We and others have shown that CCL2/CCR2 signaling is key for promoting persistent pain in the destabilization of the medial meniscus (DMM) model and that its local pharmacological blockade decreases pain behavior. These findings suggest that CCL2- CCR2 signaling locally in the joint also contributes to pain in experimental OA, highlighting the need for developing sustained local delivery methods for CCR2 inhibitors such as CCR2 receptor antagonist (CCR2RA), which is a small molecule. CCR2RA will be fused with a cationic cartilage targeting nano-construct developed for delivery of small molecules, multi-arm Avidin (mAv). The central hypothesis is that a one-time IA injection of CPC-IL-1RA and mAv-CCR2RA will provide sustained analgesic relief over 4 weeks in a rat medial meniscal transection (MMT) OA model. We have a team with expertise in OA pain and in musculoskeletal joint drug delivery that will test this hypothesis in the following aims, Aim 1: Synthesize an intra-cartilage depot for a month- long sustained release of CCR2RA using cationic mAv using hydrolysable ester linkers. Drug release rates and bioactivity of the conjugate will be measured and compared with unmodified drug in-vitro. Aim 2: Test the efficacy of a single IA injection of cationic CPC-IL-1RA and mAv-CCR2RA in the rat MMT model. Male and female rats will receive an IA injection of saline, CPC-IL-1RA, unconjugated IL-1RA, mAv-CCR2RA, or unconjugated CCR2RA. Weight-bearing asymmetry and knee hyperalgesia will be assessed; DRG changes will be evaluated by IHC and RNAscope; joint histopathology will be assessed, including assessment of knee innervation changes and immune cell infiltration. This competitive urgent revision will broaden the impact of the already designed cationic therapeutics for sustained OA pain suppression over a month with only a single IA administration thereby providing long-term pain relief, in addition to disease modification (which was addressed in the original R01).