用于潜在玻璃体内地塞米松递送的新型琥珀酰壳聚糖-地塞米松偶联物的合成和表征,International Journal of Molecular Sciences

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用于潜在玻璃体内地塞米松递送的新型琥珀酰壳聚糖-地塞米松偶联物的合成和表征
International Journal of Molecular Sciences ( IF 4.9 ) Pub Date : 2021-10-11 , DOI: 10.3390/ijms222010960
Natallia V Dubashynskaya ₁ , Anton N Bokatyi ₁ , Alexey S Golovkin ₂ , Igor V Kudryavtsev ₃ , Maria K Serebryakova ₃ , Andrey S Trulioff ₃ , Yaroslav A Dubrovskii _{2,

4} , Yury A Skorik ₁

Affiliation

玻璃体内糖皮质激素递送系统的开发是当前治疗眼后段炎性疾病的全球性挑战。这些系统的主要优点是它们可以克服眼科的解剖和生理障碍，提高局部生物利用度，同时延长和控制药物释放数月，以提高糖皮质激素治疗的安全性和有效性。开发用于玻璃体内注射的最佳递送系统的一种方法是将低分子量药物与天然聚合物结合，以防止它们快速消除并提供靶向和控制释放。本研究的重点是开发一种基于天然多糖壳聚糖 (CS) 的地塞米松 (DEX) 偶联物的两步合成程序。我们首先使用碳二亚胺化学通过琥珀酰接头将 DEX 与 CS 共轭，然后我们用琥珀酸酐修饰获得的系统，以赋予聚合物颗粒表面负 ζ 电位。所得多糖载体的 DEX 部分取代度为 2-4%，DEX 含量为 50-85 μg/mg，琥珀酰化度为 64-68%。所得颗粒的尺寸为 400-1100 nm，z 电位为 -30 至 -33 mV。pH 7.4 的体外释放研究表明，合成系统中酰胺键和酯键的水解缓慢，1 个月后 DEX 和琥珀酰地塞米松 (SucDEX) 的总释放量为 8-10%。开发的偶联物在 TNFα 诱导和 LPS 诱导的炎症模型中显示出显着的抗炎作用，分别将 THP-1 细胞中 CD54 的表达抑制 2 倍和 4 倍。因此，这些新型琥珀酰壳聚糖-地塞米松 (SucCS-DEX) 偶联物是用于玻璃体内给药的有前途的眼科载体。

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

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.

更新日期：2021-10-11

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