Cefazolin encapsulated UIO-66-NH2 nanoparticles enhance the antibacterial activity and biofilm inhibition against drug-resistant S. aureus: In vitro and in vivo studies

Abstract

Antibiotics, which are crucial to treat or prevent bacterial infections, are compounds used to kill or slow down the growth of bacteria. In recent years, antibiotic resistance has grown into a serious medical concern, so the application of controlled and targeted delivery of antibiotics to the infected site has shown excellent promises in overcoming this challenge. Towards this goal, future research must be given priority to developing novel advanced functional materials for antibiotic delivery. Metal-organic frameworks (MOFs) with remarkable functionality, high biocompatibility, crystalline structure, and high porosity have recently shown their potential as bio-carriers. UIO-66, a zirconium and terephthalic acid-based MOF, with notable chemical and physical specialties such as high stability and potential biocompatibility, has attracted much attention in drug delivery. Herein, we developed a drug delivery mechanism using UIO-66-NH2 nanoparticles that is able to load and release the antibiotic Cefazolin (CEF) over several days. The characterization and structural elucidation of nanoparticles were evaluated by BET, XRD, TGA, SEM, FT-IR, TEM, Size, Zeta potential and adsorption kinetics. In vitro release rate of CEF from UIO-66 and UI O-66-NH2 at pH 7 showed promising results over three days, 64.42 % and 78.88 %, respectively. According to N2 adsorption–desorption isotherms at 77 K, the BET surface area for UIO-66-NH2 was smaller than that of UIO-66, which is attributed to the presence of the –NH2 group. The result of XRD pattern of UIO-66-NH2 showed a peak at 20.25° attributed to existence of –NH2 on the surface of UIO-66. Also, the XRD peaks of CEF-loaded into UIO-66-NH2 indicated a peak at 28.33° was observed related to CEF. The obtained data for TGA analysis showed that UIO-66 and UIO-66-NH2 based MOFs exhibit a stability up to 400 °C after completely removing the solvent molecules (water and DMF) in the activation step. Additionally, the UIO-66-NH2 formulations showed relatively higher stability than UIO-66. Moreover, antimicrobial and antibiofilm assays were performed to assess such properties of CEF-loaded nanoparticles. The results of the broth microdilution method exhibited reduced MIC and MBC values of nanoparticles containing CEF compared to free CEF due to increased antimicrobial effect. It was also found that CEF-loaded nanoparticles have stronger antibiofilm activity than the free form of CEF, according to the results of anti-biofilm activity assays. In vitro characterization of UIO-66 and UIO-66-NH2 indicated the non-toxicity of the nanoparticles. Finally, by using the mouse incision wound model, UIO-66 and UIO-66-NH2 demonstrated promising wound healing properties. Overall, the CEF-loaded UIO-66-NH2 nanoparticles developed in this study can be considered as novel and advanced antibiotic delivery nanosystems with promising antibacterial and antibiofilm potentials both in vitro and in vivo.