*Article* **Synthesis and Characterization of Novel Succinyl Chitosan-Dexamethasone Conjugates for Potential Intravitreal Dexamethasone Delivery**

**Natallia V. Dubashynskaya <sup>1</sup> , Anton N. Bokatyi <sup>1</sup> , Alexey S. Golovkin <sup>2</sup> , Igor V. Kudryavtsev <sup>3</sup> , Maria K. Serebryakova <sup>3</sup> , Andrey S. Trulioff <sup>3</sup> , Yaroslav A. Dubrovskii 2,4 and Yury A. Skorik 1,\***


**Abstract:** The development of intravitreal glucocorticoid delivery systems is a current global challenge for the treatment of inflammatory diseases of the posterior segment of the eye. The main advantages of these systems are that they can overcome anatomical and physiological ophthalmic barriers and increase local bioavailability while prolonging and controlling drug release over several months to improve the safety and effectiveness of glucocorticoid therapy. One approach to the development of optimal delivery systems for intravitreal injections is the conjugation of lowmolecular-weight drugs with natural polymers to prevent their rapid elimination and provide targeted and controlled release. This study focuses on the development of a procedure for a two-step synthesis of dexamethasone (DEX) conjugates based on the natural polysaccharide chitosan (CS). We first used carbodiimide chemistry to conjugate DEX to CS via a succinyl linker, and we then modified the obtained systems with succinic anhydride to impart a negative ζ-potential to the polymer particle surface. The resulting polysaccharide carriers had a degree of substitution with DEX moieties of 2–4%, a DEX content of 50–85 µg/mg, and a degree of succinylation of 64–68%. The size of the obtained particles was 400–1100 nm, and the ζ-potential was −30 to −33 mV. In vitro release studies at pH 7.4 showed slow hydrolysis of the amide and ester bonds in the synthesized systems, with a total release of 8–10% for both DEX and succinyl dexamethasone (SucDEX) after 1 month. The developed conjugates showed a significant anti-inflammatory effect in TNFα-induced and LPS-induced inflammation models, suppressing CD54 expression in THP-1 cells by 2- and 4-fold, respectively. Thus, these novel succinyl chitosan-dexamethasone (SucCS-DEX) conjugates are promising ophthalmic carriers for intravitreal delivery.

**Keywords:** dexamethasone; succinyl chitosan; intravitreal delivery systems; anti-inflammatory activity
