Injectable hyaluronic acid hydrogels encapsulating drug nanocrystals for long-term treatment of inflammatory arthritis

Antiproliferative chemotherapeutic agents offer a potential effective treatment for inflammatory arthritis. However, their clinical application is limited by high systemic toxicity, low joint bioavailability as well as formulation challenges. Here, we report an intra-articular drug delivery system combining hyaluronic acid hydrogels and drug nanocrystals to achieve localized and sustained delivery of an antiproliferative chemotherapeutic agent camptothecin for long-term treatment of inflammatory arthritis. We synthesized a biocompatible, in situ-forming injectable hyaluronic acid hydrogel using a naturally occurring click chemistry: cyanobenzothiazole/cysteine reaction, which is the last step reaction in synthesizing D-luciferin in fireflies. This hydrogel was used to encapsulate camptothecin nanocrystals (size of 160-560 nm) which released free camptothecin in a sustained manner for 4 weeks. In vivo studies confirmed that the hydrogel remained in the joint over 4 weeks. By using the collagen-induced arthritis rat model, we demonstrate that the hydrogel-camptothecin formulation could alleviate arthritis severity as indicated by the joint size and interleukin-1 beta level in the harvested joints, as well as from histological and microcomputed tomography evaluation of joints. The hydrogel-nanocrystal formulation strategy described here offers a potential solution for intra-articular therapy for inflammatory arthritis.