Light‐Mediated Delivery of Dexamethasone for the Treatment of Rheumatoid Arthritis

Abstract

Introduction 50 million patients are diagnosed with arthritis yearly, with a total of 20% of the nation suffering from this ailment. No curative treatment for arthritis currently exists, only therapeutics that mitigate its symptoms while inducing severe side effects from chronic systemic exposure. The current inadequacy of treatment highlights the need for innovative drug delivery methods. We have developed a photosensitive method of drug delivery that can be spatiotemporally controlled to treat arthritis and reduce systemic exposure to therapeutics, such as dexamethasone, that cause severe side effects. We hypothesize that by conveying a photo‐responsive vitamin B12‐dexamethasone (B12‐dex) conjugate within red blood cells (RBCs) we will be able to localize delivery of dex, treat arthritis with an overall lower amount of dex, and diminish systemic exposure. Methods and Results Alkyl‐cobalamin derivatives of vitamin B12 are known to contain an intrinsically photosensitive axial cobalt‐carbon bond. We employed this property to create a light responsive drug platform that is conveyed throughout the circulatory system by RBCs. First, we have demonstrated that the B12‐drug phototherapeutic agents can be loaded via a hypotonic swelling protocol and trapped within RBCs due to the membrane impermeability of B12. Second, we installed a Cy5 “antenna” on B12, enabling the phototherapeutic to respond to long wavelength (650 nm) tissue‐penetrating light. Third, we employed intravital imaging to demonstrate that RBC‐conveyed phototherapeutics are retained in circulation for up to 2 hours, whereas free B12‐drug conjugates rapidly diffuse into surrounding tissue. Building off of these results, we synthesized and loaded a B12‐dex conjugate into RBCs and investigated the therapeutic efficacy of this agent using a collagen antibody induced mouse model of arthritis. Arthritic mice were treated with intraperitoneal (IP) dex at a standard dose, B12‐dex RBCs, and B12‐water RBCs. Dex or water from B12‐drug RBCs was released locally to the arthritic paw via a 650 nm 3 mW laser. As expected, standard of care dex caused arthritis to go into remission while B12‐water RBCs did not treat arthritis. However, B12‐dex RBCs also successfully induced remission of arthritis with a 3‐fold lower dose of dex relative to IP dex. Thus, we successfully treated arthritic mice using B12‐dex RBCs while systemically delivering a much lower dose to achieve comparable remission to IP dex treatment. Conclusions We have demonstrated that B12‐dex, conveyed by RBCs, offers a novel method for the treatment of arthritis. This technology potentially addresses three key limitations of current arthritis therapy: (1) the inability to selectively deliver high quantities of a drug to the inflamed joint, (2) moderate to severe systemic side effects from long‐term exposure, and (3) the inability to direct therapeutics in a patient‐directed fashion. Future work will further probe the issue of selectivity and side effects by investigating the therapeutic index of B12‐dex as ...