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

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 low-molecular-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 z-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.

Cyclodextrin Stabilized Freeze-Dried Silica/Chitosan Nanoparticles for Improved Terconazole Ocular Bioavailability

“…Polysaccharides are widely used as ocular drug delivery carriers [ 36 , 37 ]. Chitosan HCl is a mucoadhesive cationic polysaccharide polymer with considerable capability for topical ocular drug delivery [ 38 ].…”

From Static to Dynamic: A Review on the Role of Mucus Heterogeneity in Particle and Microbial Transport

“…The degradation process is also dependent on the molecular weight of chitosan derivatives during mucus clearance, suggesting that the physical motion between mucus and chitosan might play an extra role on degradation. There are many other chitosan derivatives, including trimethyl chitosan, , carboxymethyl chitosan, − thiolated chitosan, − acrylated chitosan, − half-acetylated chitosan, , glycol chitosan, − chitosan conjugates, − chitosan–catechol, , methylpyrrolidinone chitosan, , cyclodextrin–chitosan − and oleoyl-quaternized chitosan, that enhance the mucoadhesive properties and improve the particle transport through the McLs. Airway and intestinal mucosal organoids along with oral mucosal organoids have great potential for high-efficient drug delivery system design.…”

Fluorescent Nanosystems for Drug Tracking and Theranostics: Recent Applications in the Ocular Field

“…In this respect, the use of chitosan to improve the delivery of drugs into the eye tissues for its properties as a mucoadhesive agent, controlled drug release and permeation enhancer is interesting [ 24 ]. It is used in conjugation with a drug, such as in the study of Dubashynskaya et al, to improve the intravitreal delivery of dexamethasone [ 109 ]. In the major cases, it was used as a coating of nanocarriers to promote intraocular penetration, as reported by which designed modified NLCs with three different types of chitosan: chitosan acetyl-L-cysteine (CS-NAC), chitosan oligosaccharides (COS) and carboxymethyl chitosan (CMCS).…”

“…Moreover, rapid clearance remains a challenge for nanosystems as they need to release their payload before being eliminated from the eye. Many studies focus on assessing the distribution in various tissues once the formulation has been instilled into the eye [ 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 , 134 , 137 , 138 , 139 ]. Unfortunately, few studies focus on assessing how mechanisms including blinking, tear drainage and ocular metabolism may interact with nanosystems [ 66 , 115 ].…”