Osteoarthritis (OA) is the most common joint arthritis affecting more than 500 milion peoples worldwide. No intra-articular disease-modifying osteoarthritis drug (DMOAD) has yet passed successful clinical trials due to low therapeutic outcomes, caused by short joint retention time and a lack of cartilage targeting. Intra-articular delivery systems are necessary to extend the joint retention time.

Targeting the cartilage matrix requires nanosized (< 20 nm) delivery systems having a positive charge, able to penetrate deeply through the porous cartilage.This thesis aimed to design different types of biodegradable and biocompatible cationic intra-articular formulations delivering DMOADs to the anionic extracellular matrix of cartilage. Firstly, an avidin-based system (< 10 nm) was synthesized to ensure cartilage matrix uptake and retention of kartogenin via electrostatic interactions. Secondly DOTAP-based liposomes (> 100 nm) were formulated via a microfluidic system to ensure cartilage matrix surface retention and extended delivery of lorecivivint. These two cartilage-targeting strategies were further combined to create avidin-coated liposomes. Ex vivo experiments on bovine cartilage explants demonstrated size-dependent cartilage uptake for the two technologies. In particular, avidin-based technology demonstrated high cartilage uptake and retention in both physiological and simulated synovial fluid environments.

In vivo experiments in anterior cruciate ligament transection (ACLT) rat model were performed to investigate the safety and efficiency of both drug delivery systems.The thesis concludes with a discussion of some alternative therapeutic approaches and potential perspectives. Overall, this work provides proofs-of-concept of novel and innovative cartilage delivering systems with the potential to treat human OA.