title: Hyaluronidase-sensitive nanoparticle templates for triggered release of HIV/AIDS microbicide in vitro.
abstract: This study was designed to test the hypothesis that a triggered release of a topical microbicide (tenofovir) from hyaluronic acid nanoparticles (HA-NPs) can be achieved under the influence of hyaluronidase (HAase) enzyme. A fractional factorial experimental design was used to examine the factors [molar concentrations of adipic acid dihydrazide (X1) and 1-ethyl-3-[3-dimethylaminopropyl] carbodiimide hydrochloride (X2), volume of acetone (X3) and reaction time (X4)] influencing the responses, Y1; particle mean diameter: PMD (nanometers: nm), Y2; polydispersity index: PDI and Y3; zeta (ζ) potential: (millivolts). The amide bond formation between HA and ADH after cross-linking was confirmed by FT-IR and (13)C-NMR analyses. These NPs were also characterized for cytotoxicity on a human vaginal epithelial cell line and L. crispatus. When formulated with factors X1; 2.49 mM, X2; 9.96 mM, X3; 60 mL, X4; 6 h, HA-NPs exhibited a spherical shape with PMD, PDI, ζ potential, encapsulation efficiency, and drug loading of 70.6 ± 4.1 nm, 0.07 ± 0.02, -38.2 ± 2.8 mV, 51.8 ± 2.4% w/w and 26.1 ± 1.2% w/w, respectively, (n = 3). Unlike for HA based gel, HAase significantly triggered the drug release and HA degradation from the NPs after 24 h (~90% w/w and 65% w/w, respectively); whereas, in its absence, these values were ~39% w/w and 26% w/w, respectively. The NPs were non-cytotoxic to human vaginal VK2/E6E7, End1/E6E7 cells and Lactobacillus crispatus. These data highlight the potential of HAase-sensitive HA-NPs templates for the controlled and vaginal delivery of anti-HIV/AIDS microbicides.
authors.affiliation: Laboratory of Future Nanomedicines and Theoretical Chronopharmaceutics, Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, 2464 Charlotte Street, Kansas City, Missouri, 64108, USA.
authors.forename: Vivek
authors.initials: V
authors.lastname: Agrahari
authors.forename: Chi
authors.initials: C
authors.lastname: Zhang
authors.forename: Tao
authors.initials: T
authors.lastname: Zhang
authors.forename: Wenjing
authors.initials: W
authors.lastname: Li
authors.forename: Todor K
authors.initials: TK
authors.lastname: Gounev
authors.forename: Nathan A
authors.initials: NA
authors.lastname: Oyler
authors.forename: Bi-Botti C
authors.initials: BB
authors.lastname: Youan
mesh_terms: D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D002460:Cell Line; D005260:Female; D006801:Humans; D006821:Hyaluronoglucosaminidase / Q000378:metabolism*; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D053758:Nanoparticles; D017550:Spectroscopy, Fourier Transform Infrared; D013499:Surface Properties; D014621:Vagina / Q000166:cytology / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D006821:Hyaluronoglucosaminidase