Cationic Peptide Carriers enable Long Term Delivery of Insulin-Like Growth Factor-1 to Suppress Osteoarthritis Induced Matrix Degradation

Abstract

Background. Insulin-like growth factor-1 (IGF-1) has the potential to be used for osteoarthritis (OA) treatment but has not been evaluated in clinics yet owing to toxicity concerns. It suffers from short intra-joint residence time and a lack of cartilage targeting following its intra-articular administration. Here we synthesize an electrically charged cationic formulation of IGF-1 by using a short-length arginine-rich, hydrophilic cationic peptide carrier (CPC) with a net charge of + 14, designed for rapid and high uptake and retention in both healthy and arthritic cartilage. Methods. IGF-1 was conjugated to CPC by using a site-specific sulfhydryl reaction via a bifunctional linker. Intra-cartilage depth of penetration and retention of CPC-IGF-1 was compared with the unmodified IGF-1. The therapeutic effectiveness of a single dose of CPC-IGF-1 was compared with free IGF-1 in an IL-1α challenged cartilage explant culture OA model. Results. CPC-IGF-1 rapidly penetrated through the full thickness of cartilage creating a drug depot owing to electrostatic interactions with negatively charged aggrecan-glycosaminoglycans (GAGs). CPC-IGF-1 remained bound within the tissue while unmodified IGF-1 cleared out. Treatment with a single dose of CPC-IGF-1 effectively suppressed IL-1α induced GAG loss and nitrite release, and rescued cell metabolism and viability throughout the 16-day culture period, while free IGF at the equivalent dose was not effective. Conclusions. CPC-mediated delivery of IGF-1 can enable its clinical use for OA treatment with only a single dose. CPC is a versatile cationic motif that can be used for intra-cartilage delivery of other similar-sized drugs.