ε-Poly-l-lysine as an efficient cartilage penetrating and residing drug carrier with high intraarticular injection safety for treating osteoarthritis

[Display omitted] •ε-PLL is identified as a safe and efficient cationic macromolecular carrier for drug delivery to cartilage.•ε-PLL can bind cartilage matrix trough reversibly electrostatic interaction.•Intra-articular injection of ε-PLL exhibits excellent biosafety.•ε-PLL significantly improves kartogenin availability for osteoarthritis therapy. A major reason that hinders the clinical application of disease-modifying osteoarthritis drugs (DMOADs) is the unmet challenges in their effective delivery to cartilage. Cationic macromolecules represent promising carriers to enhance the drug delivery to cartilage through their electrostatic interaction with the negatively charged cartilage matrix. However, current candidate cationic macromolecular carriers (CMCs) must solve the intractable challenges in scalable production and biosafety before they can be used clinically. ε-poly-l-lysine (ε-PLL) is a unique poly (amino acid) that has favorable features to conquer the above issues. In this study, we evaluated the potential of ε-PLL as a cost effectiveness, biosafety, and effective CMC for drug delivery to cartilage. Cartilage explant from pig knee was used as a model for the in vitro analysis of ε-PLL’s interaction with, penetration into, and resident in cartilage tissue. The results showed that ε-PLL had a strong distribution tendency in cartilage with partition coefficient K ∼ 4.3 and weak cartilage matrix binding ability (KD ∼ 310 μM) with abundant intra-cartilage binding sites (N ∼ 9900 μM). Furthermore, ε-PLL could also penetrate full thickness cartilage and showed a long-time retention in cartilage explants and mouse joint cavity. The results of in vitro and in vivo toxicity tests showed nearly no negative impact of ε-PLL (100 μg/mL) on chondrocytes or local tissue. Using kartogenin (KGN, a potential DMOAD) as a model drug, the effectiveness of ε-PLL to improve the drug bioavailability in a mouse OA model was proved. Together, these results suggest that ε-PLL can be used as an effective and safe CMC for effective DMOAD delivery to cartilage.