ABSTRACT Rheumatoid arthritis (RA) is a common autoimmune disease, which can cause devastating joint destruction and generalized and localized osteoporosis. Generally, there is no cure for RA, although a variety of drugs can reduce inflammation and joint destruction, including chloroquine (CQ) and hydroxychloroquine (HCQ). Many anti-RA drugs have severe side effects, for example CQ can result in renal toxicity and blindness in up to 0.5- 1% of patients. HCQ has a slightly lower toxicity profile and for this reason it replaced CQ for the treatment of RA in the US and Europe many years ago. We reported recently that CQ, but not HCQ, prevents bone resorption and osteoporosis in mouse models of postmenopausal osteoporosis and hyperparathyroidism. An attractive strategy to minimize side effects of drugs used to treat bone diseases is to administer them in a form that targets them to bone. This could allow drugs to be given to patients at doses with reduced risk of side effects, while also delivering effective concentrations specifically to bone. Based on the high bone affinity of bisphosphonates (BPs) that are currently used to osteoporosis, we have generated a Bone-Targeted CQ (BTCQ) analog using a BP that binds avidly to bone, but does not inhibit bone resorption, which we attached to CQ through degradable carbamate linker chemistry. We have confirmed that BTCQ has high affinity for bone and high potency to inhibit osteoclast formation and bone resorption at 3-10-fold lower concentrations than CQ in vitro. It also inhibited PTH-induced bone resorption in vivo in mice at significantly lower concentrations than CQ. We now plan to: 1) Scale up the existing synthetic route, optimize purification methods to prepare sufficient quantities of BTCQ for examination of its in vivo efficacy in an animal model of RA and test the distribution and cellular localization of fluorescently-labeled bisphosphonates in vivo as an early mechanistic approximation of the PK of BTCQ and potentially of the released CQ; 2) Examine the efficacy of these novel BTCQ conjugates to prevent the development of joint inflammation and destruction in a TNF transgenic mouse model of RA. Success with these studies could then lead to the development of a novel therapy for RA patients and later to the generation of other types of bone-targeted drugs, including chemotherapeutics and antibiotics, using this new conjugation technology.