Alkholief Musaed, Kalam Mohd Abul, Raish Mohammad, Ansari Mushtaq Ahmad, Alsaleh Nasser B, Almomen Aliyah, Ali Raisuddin, Alshamsan Aws
Department of Pharmaceutics, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.
Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.
Pharmaceutics. 2023 Sep 3;15(9):2273. doi: 10.3390/pharmaceutics15092273.
Uveitis is an ocular illness that if not treated properly can lead to a total loss of vision. In this study, we evaluated the utility of HA-coated Dexamethasone-sodium-phosphate (DEX)-chitosan nanoparticles (CSNPs) coated with hyaluronic acid (HA) as a sustained ocular delivery vehicle for the treatment of endotoxin-induced-uveitis (EIU) in rabbits. The CSNPs were characterized for particle size, zeta potential, polydispersity, surface morphology, and physicochemical properties. Drug encapsulation, in vitro drug release, and transcorneal permeation were also evaluated. Finally, eye irritation, ocular pharmacokinetics, and pharmacodynamics were in vivo. The CSNPs ranged from 310.4 nm and 379.3 nm pre-(uncoated) and post-lyophilization (with HA-coated), respectively. The zeta potentials were +32 mV (uncoated) and -5 mV (HA-uncoated), while polydispersity was 0.178-0.427. Drug encapsulation and loading in the CSNPs were 73.56% and 6.94% (uncoated) and 71.07% and 5.54% (HA-coated), respectively. The in vitro DEX release over 12 h was 77.1% from the HA-coated and 74.2% from the uncoated NPs. The physicochemical properties of the CSNPs were stable over a 3-month period when stored at 25 °C. Around a 10-fold increased transcorneal-flux and permeability of DEX was found with HA-CSNPs compared to the DEX-aqueous solution (DEX-AqS), and the eye-irritation experiment indicated its ocular safety. After the ocular application of the CSNPs, DEX was detected in the aqueous humor (AH) till 24 h. The area under the concentrations curve (AUC) for DEX from the CSNPs was 1.87-fold (uncoated) and 2.36-fold (HA-coated) higher than DEX-AqS. The half-life (t) of DEX from the uncoated and HA-coated NPs was 2.49-and 3.36-fold higher, and the ocular MRT was 2.47- and 3.15-fold greater, than that of DEX-AqS, respectively. The EIU rabbit model showed increased levels of MPO, TNF-α, and IL-6 in AH. Topical DEX-loaded CSNPs reduced MPO, TNF-α, and IL-6 levels as well as inhibited NF-κB expression. Our findings demonstrate that the DEX-CSNPs platform has improved the delivery properties and, hence, the promising anti-inflammatory effects on EIU in rabbits.
葡萄膜炎是一种眼部疾病，若治疗不当可导致完全失明。在本研究中，我们评估了用透明质酸（HA）包被的地塞米松磷酸钠（DEX）-壳聚糖纳米粒（CSNPs）作为一种持续性眼部给药载体治疗兔内毒素诱导性葡萄膜炎（EIU）的效用。对CSNPs的粒径、zeta电位、多分散性、表面形态和理化性质进行了表征。还评估了药物包封、体外药物释放和角膜透过性。最后，进行了眼刺激性、眼部药代动力学和药效学的体内研究。CSNPs冻干前（未包被）和冻干后（HA包被）的粒径分别为310.4 nm和379.3 nm。zeta电位分别为+32 mV（未包被）和-5 mV（HA未包被），而多分散性为0.178 - 0.427。CSNPs中药物的包封率和载药量分别为73.56%和6.94%（未包被）以及71.07%和5.54%（HA包被）。HA包被的CSNPs在12小时内的体外DEX释放率为77.1%，未包被的纳米粒为74.2%。CSNPs的理化性质在25℃储存3个月期间保持稳定。与DEX水溶液（DEX-AqS）相比，HA-CSNPs使DEX的角膜通量和渗透率提高了约10倍，眼刺激性实验表明其眼部安全性良好。眼部应用CSNPs后，在房水（AH）中直至24小时都能检测到DEX。CSNPs中DEX的浓度曲线下面积（AUC）比DEX-AqS高1.87倍（未包被）和2.36倍（HA包被）。未包被和HA包被的纳米粒中DEX的半衰期（t）分别比DEX-AqS高2.49倍和3.36倍，眼部平均驻留时间分别比DEX-AqS长2.47倍和3.15倍。EIU兔模型显示AH中MPO、TNF-α和IL-6水平升高。局部应用载有DEX的CSNPs可降低MPO、TNF-α和IL-6水平，并抑制NF-κB表达。我们的研究结果表明，DEX-CSNPs平台改善了给药性能，因此对兔EIU具有有前景的抗炎作用。
