Costabile Gabriella, Mitidieri Emma, Visaggio Daniela, Provenzano Romina, Miro Agnese, Quaglia Fabiana, d'Angelo Ivana, Frangipani Emanuela, Sorrentino Raffaella, Visca Paolo, d'Emmanuele di Villa Bianca Roberta, Ungaro Francesca
Department of Pharmacy, School of Medicine, University of Napoli Federico II, Napoli, Italy.
Department of Science, University Roma Tre, Rome, Italy; Fondazione Santa Lucia IRCCS, Rome, Italy.
Int J Pharm. 2022 Dec 15;629:122400. doi: 10.1016/j.ijpharm.2022.122400. Epub 2022 Nov 13.
The potential of intra-venous gallium nitrate (GaN) administration against Pseudomonas aeruginosa pneumonia was recently demonstrated in mice and in cystic fibrosis (CF) patients. Likewise, the added value of direct lung delivery of Ga(III) has been shown in rats. Therefore, the design of a drug delivery system specifically engineered for Ga(III) inhalation is imperative to improve its accumulation in lungs. To this purpose, Ga(III) was efficiently encapsulated into hyaluronic acid/chitosan nanoparticles (Ga_HA/CS NPs), whose features were tuned to facilitate access to the target by overcoming mucus and biofilm surrounding bacteria. Then, to improve in vivo lung deposition, Ga_HA/CS NPs were engineered into mannitol-based NEM (Ga_Man NEM). The powders showed optimal in vitro aerosol performance, and sustained release kinetics in lung lining fluids. Moreover, good tolerability and antimicrobial properties were shown in vitro. Intratracheal insufflation of Ga_Man NEM in rats resulted in a significant improvement of Ga(III) persistence in the lungs coupled to a lower Ga(III) concentration in plasma and urine, compared to GaN solution. Noteworthy, the developed formulation significantly modifies the unfavorable Ga(III) kinetic increasing the Ga(III) to the lung and preventing Ga(III) accumulation in the kidney, key responsible for adverse effects, conclusively demonstrating the benefit of Ga_Man NEM to exploit the therapeutic effect of Ga(III) via inhalation route.
最近在小鼠和囊性纤维化（CF）患者中证实了静脉注射硝酸镓（GaN）治疗铜绿假单胞菌肺炎的潜力。同样，在大鼠中也显示了直接肺部递送Ga(III)的附加价值。因此，设计一种专门为Ga(III)吸入而设计的药物递送系统对于提高其在肺部的蓄积至关重要。为此，Ga(III)被有效地封装到透明质酸/壳聚糖纳米颗粒（Ga_HA/CS NPs）中，其特性经过调整以克服围绕细菌的黏液和生物膜，从而便于到达靶点。然后，为了改善体内肺部沉积，将Ga_HA/CS NPs设计成基于甘露醇的纳米工程微粒（Ga_Man NEM）。这些粉末在体外显示出最佳的气溶胶性能，以及在肺衬液中的缓释动力学。此外，在体外还显示出良好的耐受性和抗菌性能。与GaN溶液相比，在大鼠中气管内注入Ga_Man NEM导致肺部Ga(III)持久性显著提高，同时血浆和尿液中的Ga(III)浓度降低。值得注意的是，所开发的制剂显著改变了不利的Ga(III)动力学，增加了Ga(III)在肺部的含量，并防止Ga(III)在肾脏中蓄积，而肾脏是不良反应的关键所在，最终证明了Ga_Man NEM通过吸入途径利用Ga(III)治疗效果的益处。
