Department of Biomedical Engineering, University of Southern California, Los Angeles, CA, USA.
Department of Medicine, Division of Nephrology and Hypertension, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; USC/UKRO Kidney Research Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
J Control Release. 2021 Jan 10;329:1198-1209. doi: 10.1016/j.jconrel.2020.10.047. Epub 2020 Oct 28.
Nanoparticle drug delivery has many advantages over small molecule therapeutics, including reducing off-target side effects and increasing drug potency. However, many nanoparticles are administered parenterally, which is challenging for chronic diseases such as polycystic kidney disease (PKD), the most common hereditary disease worldwide in which patients need continuous treatment over decades. To address this clinical need, we present the development of nanoparticles synthesized from chitosan, a widely available polymer chosen for its ability to improve oral bioavailability. Specifically, we optimized the synthesis parameters of chitosan nanoparticles and demonstrate mucoadhesion and permeation across an intestinal barrier model in vitro. Furthermore, when administered orally to mice, ex vivo imaging of rhodamine-loaded chitosan nanoparticles showed significantly higher accumulation in the intestines compared to the free model drug, as well as 1.3 times higher serum area under the curve (AUC), demonstrating controlled release and improved serum delivery over 24 h. To test its utility for chronic diseases such as PKD, we loaded the candidate PKD drug, metformin, into chitosan nanoparticles, and upon oral administration to a PKD murine model (Pkd1;Pax8-rtTA;Tet-O cre), a lower cyst burden was observed compared to free metformin, and was well tolerated upon repeated dosages. Blood urea nitrogen (BUN) and creatinine levels were similar to untreated mice, demonstrating kidney and biocompatibility health. Our study builds upon previous chitosan-based drug delivery approaches, and demonstrates a novel, oral nanoformulation for PKD.
纳米药物传递相对于小分子治疗具有许多优势，包括减少脱靶副作用和提高药物效力。然而，许多纳米颗粒是通过注射给药的，这对慢性疾病如多囊肾病（PKD）具有挑战性，PKD 是全球最常见的遗传性疾病，患者需要数十年的持续治疗。为了满足这一临床需求，我们开发了由壳聚糖合成的纳米颗粒，壳聚糖是一种广泛使用的聚合物，因其能够提高口服生物利用度而被选择。具体而言，我们优化了壳聚糖纳米颗粒的合成参数，并在体外证明了其对肠道屏障模型的粘膜粘附性和渗透性。此外，当以口服方式给予小鼠时，负载罗丹明的壳聚糖纳米颗粒的离体成像显示，与游离模型药物相比，在肠道中的积累显著增加，血清曲线下面积（AUC）也增加了 1.3 倍，表明 24 小时内的控制释放和改善的血清传递。为了测试其在 PKD 等慢性疾病中的用途，我们将候选 PKD 药物二甲双胍载入壳聚糖纳米颗粒中，并在 PKD 小鼠模型（Pkd1; Pax8-rtTA; Tet-O cre）中进行口服给药，与游离二甲双胍相比，观察到较低的囊肿负担，并且在重复剂量下耐受性良好。血尿素氮（BUN）和肌酐水平与未治疗的小鼠相似，表明肾脏和生物相容性良好。我们的研究建立在以前的壳聚糖为基础的药物传递方法的基础上，并展示了一种用于 PKD 的新型口服纳米制剂。
