Abstract
Nanoparticle deployment in drug delivery is contingent upon controlled drug loading and a desired release profile, with simultaneous biocompatibility and cellular targeting. Iron oxide nanoparticles (IONPs), being biocompatible, are used as drug carriers. However, to prevent aggregation of bare IONPs, they are coated with stabilizing agents. We hypothesize that, zwitterionic drugs like norfloxacin (NOR, a fluoroquinolone) can manifest dual functionality – nanoparticle stabilization and antibiotic activity, eliminating the need of a separate stabilizing agent. Since these drugs have different charges, depending on the surrounding pH, drug loading enhancement could be pH dependent. Hence, upon synthesizing IONPs, they were coated with NOR, either at pH 5 (predominantly as cationic, NOR+) or at pH 10 (predominantly as anionic, NOR−). We observed that, drug loading at pH 5 exceeded that at pH 10 by 4.7–5.7 times. Furthermore, only the former (pH 5 system) exhibited a desirable slower drug release profile, compared to the free drug. NOR-coated IONPs also enable a 22 times higher drug accumulation in macrophages, compared to identical extracellular concentrations of the free drug. Thus, lowering the drug coating pH to 5 imparts multiple benefits – improved IONP stability, enhanced drug coating, higher drug uptake in macrophages at reduced toxicity and slower drug release.
Highlights
Nanoparticles have taken the center-stage in drug delivery applications, wherein they can improve drug pharmacokinetics and pharmacodynamics and may increase drug accumulation in both animal cells and bacteria, proving beneficial to overcome drug resistance [1,2]
Uncoated iron oxide nanoparticles (UIONPs) exhibited a hydrodynamic diameter greater than 1000 nm, which was due to the aggregation of ≈10 nm individual UIONPs, as observed by transmission electron microscopy (TEM) (Figure 2a,b)
The relative viability of NOR, NOR@IONPpH5 and NOR@IONPpH10 for 32 μg/mL drug concentration are found to be 102.1, 107.5 and 30.1%, respectively. Both NOR and NOR@IONPpH5 administered at this concentration, exert no toxicity towards the macrophage cells. This is in accordance with our previous study [30] on macrophages, where we reported that the NOR becomes toxic at concentrations greater than 100 μg/mL, while the toxicity of Iron oxide nanoparticles (IONPs) greatly increases above concentrations of 1 mg/mL
Summary
Nanoparticles have taken the center-stage in drug delivery applications, wherein they can improve drug pharmacokinetics and pharmacodynamics and may increase drug accumulation in both animal cells and bacteria, proving beneficial to overcome drug resistance [1,2]. A shift observed in the FTIR peak for OH stretching from 3420 cm−1 to 3440 cm−1 (Supporting Information File 1, Figure S2) could be a result of changes in the intermolecular H bonding, whereby we believe that a fraction of the hydrogen bonding in NOR@IONPpH10 could occur through the amine groups present in NOR and the negatively charged IONPs at pH10 during drug coating. Comparing the different nanoparticles synthesized, i.e., UIONPs, NOR@IONPpH5 and NOR@IONPpH10, we observed that the drug coated IONPs have a much lower aggregate size with a reduced hydrodynamic size distribution (Table 1).
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