Tenofovir Containing Thiolated Chitosan Core/Shell Nanofibers: In Vitro and in Vivo Evaluations

• Published in: Molecular pharmaceutics Vol. 13; no. 12; pp. 4129 - 4140
• Main Authors: Meng, Jianing, Agrahari, Vivek, Ezoulin, Miezan J, Zhang, Chi, Purohit, Sudhaunshu S, Molteni, Agostino, Dim, Daniel, Oyler, Nathan A, Youan, Bi-Botti C
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 05.12.2016
• Subjects: Animals; Cells, Cultured; Chitosan - administration & dosage; Chitosan - chemistry; Drug Delivery Systems; Drug Liberation; Female; Humans; Inflammation - drug therapy; Inflammation - pathology; Keratinocytes - cytology; Keratinocytes - drug effects; Mice; Mice, Inbred C57BL; Nanofibers - administration & dosage; Nanofibers - chemistry; Nanoparticles - administration & dosage; Nanoparticles - chemistry; Reverse Transcriptase Inhibitors - chemistry; Reverse Transcriptase Inhibitors - pharmacology; Sulfhydryl Compounds - chemistry; Tenofovir - chemistry; Tenofovir - pharmacology; drug loading; coaxial electrospinning; mucoadhesion; water-soluble drug; nanofiber
• ISSN: 1543-8384; 1543-8392
• DOI: 10.1021/acs.molpharmaceut.6b00739

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 2 = 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.