Meng Jianing, Agrahari Vivek, Ezoulin Miezan J, Zhang Chi, Purohit Sudhaunshu S, Molteni Agostino, Dim Daniel, Oyler Nathan A, Youan Bi-Botti C
Laboratory of Future Nanomedicines and Theoretical Chronopharmaceutics Division of Pharmaceutical Sciences, University of Missouri-Kansas City , Kansas City, Missouri 64108, United States.
Department of Chemistry, University of Missouri-Kansas City , Kansas City, Missouri 64110, United States.
Mol Pharm. 2016 Dec 5;13(12):4129-4140. doi: 10.1021/acs.molpharmaceut.6b00739. Epub 2016 Nov 1.
It is hypothesized that thiolated chitosan (TCS) core/shell nanofibers (NFs) can enhance the drug loading of tenofovir, a model low molecular weight and highly water-soluble drug molecule, and improve its mucoadhesivity and in vivo safety. To test this hypothesis, poly(ethylene oxide) (PEO) core with TCS and polylactic acid (PLA) shell NFs are fabricated by a coaxial electrospinning technique. The morphology, drug loading, drug release profiles, cytotoxicity and mucoadhesion of the NFs are analyzed using scanning and transmission electron microscopies, liquid chromatography, cytotoxicity assays on VK2/E6E7 and End1/E6E7 cell lines and Lactobacilli crispatus, fluorescence imaging and periodic acid colorimetric method, respectively. In vivo safety studies are performed in C57BL/6 mice followed by H&E and immunohistochemical (CD45) staining analysis of genital tract. The mean diameters of PEO, PEO/TCS, and PEO/TCS-PLA NFs are 118.56, 9.95, and 99.53 nm, respectively. The NFs exhibit smooth surface. The drug loading (13%-25%, w/w) increased by 10-fold compared to a nanoparticle formulation due to the application of the electrospinning technique. The NFs are noncytotoxic at the concentration of 1 mg/mL. The PEO/TCS-PLA core/shell NFs mostly exhibit a release kinetic following Weibull model (r = 0.9914), indicating the drug release from a matrix system. The core/shell NFs are 40-60-fold more bioadhesive than the pure PEO based NFs. The NFs are nontoxic and noninflammatory in vivo after daily treatment for up to 7 days. Owing to their enhanced drug loading and preliminary safety profile, the TCS core/shell NFs are promising candidates for the topical delivery of HIV/AIDS microbicides such as tenofovir.
据推测，硫醇化壳聚糖（TCS）核/壳纳米纤维（NFs）可以提高替诺福韦（一种低分子量且高度水溶性的模型药物分子）的载药量，并改善其粘膜粘附性和体内安全性。为了验证这一假设，采用同轴静电纺丝技术制备了具有TCS的聚环氧乙烷（PEO）核和聚乳酸（PLA）壳的纳米纤维。分别使用扫描电子显微镜和透射电子显微镜、液相色谱、对VK2/E6E7和End1/E6E7细胞系以及卷曲乳杆菌进行细胞毒性测定、荧光成像和高碘酸比色法，分析纳米纤维的形态、载药量、药物释放曲线、细胞毒性和粘膜粘附性。在C57BL/6小鼠中进行体内安全性研究，随后对生殖道进行苏木精-伊红（H&E）染色和免疫组织化学（CD45）染色分析。PEO、PEO/TCS和PEO/TCS-PLA纳米纤维的平均直径分别为118.56、9.95和99.53nm。纳米纤维表面光滑。由于采用了静电纺丝技术，载药量（13%-25%，w/w）比纳米颗粒制剂提高了10倍。纳米纤维在浓度为1mg/mL时无细胞毒性。PEO/TCS-PLA核/壳纳米纤维大多呈现符合威布尔模型的释放动力学（r = 0.9914），表明药物从基质系统中释放。核/壳纳米纤维的生物粘附性比纯PEO基纳米纤维高40-60倍。在每天治疗长达7天后，纳米纤维在体内无毒且无炎症。由于其载药量增加和初步的安全性，TCS核/壳纳米纤维有望成为替诺福韦等艾滋病毒/艾滋病杀微生物剂局部给药的候选材料。
