Magnetically targeted co-delivery of hydrophilic and hydrophobic drugs with hollow mesoporous ferrite nanoparticles

Abstract

A magnetically targeted drug delivery system (DDS) is developed to solve the delivery problem of hydrophobic drugs by using hollow mesoporous ferrite nanoparticles (HMFNs). The HMFNs are synthesized by a one-pot hydrothermal method based on the Ostwald ripening process. The biocompatibility of the synthesized HMFNs was determined by MTT assay, lactate dehydrogenase (LDH) leakage assay and hemolyticity against rabbit red blood cells. Moreover, Prussian blue staining and bio-TEM observations showed that the cell uptake of nanocarriers was in a dose and time-dependent manner, and the nanoparticles accumulate mostly in the cytoplasm. A typical highly hydrophobic anti-tuberculosis drug, rifampin (RFP) was loaded into HMFNs using supercritical carbon dioxide (SC-CO₂) impregnation, and the drug loading amount reached as high as 18.25 wt%. In addition, HMFNs could co-encapsulate and co-deliver hydrophobic (RFP) and hydrophilic (isoniazide, INH) drugs simultaneously. The in vitro release tests demonstrated extra sustained co-release profiles of rifampicin and isoniazide from HMFNs. Based on this novel design strategy, the co-delivery of drugs in the same carrier enables a drug delivery system with efficient enhanced chemotherapeutic effect.

Fig. 1. Schematic illustration of the formation procedure of magnetically targeted drug delivery systems co-loading/co-delivery of hydrophobic and hydrophilic agents.

Fig. 2. (a) Low-magnification SEM image of the HMFNs, (b) the corresponding particle size distribution of the HMFNs, (c) high-magnification SEM image of the HMFNs, the arrows indicate the broken spheres of the HMFNs (d) TEM image of the HMFNs.

Fig. 3. (a) XRD pattern of the HMFNs, (b) nitrogen adsorption/desorption isotherm and BJH pore plot (inset) of the HMFNs.

Fig. 4. (a) The proliferation of L929 cells treated with HMFNs for 24, 48 and 72 h; (b) LDH leakage of L929 cells treated with HMFNs; (c) percentage of hemolysis of RBCs incubated with HMFNs at different concentrations ranging from 25 to 200 μg ml⁻¹ for 3 h (inset: photographic images for direct observation of hemolysis by HMFNs, using water as a positive control and PBS as a negative control, and HMFNs suspensions of different concentrations). Data represent means ± SD (n = 6). *Statistically significant difference as compared to the controls (p < 0.05 for each).

Fig. 5. Bio-TEM images of HMFNs uptake by L929 cells. (a) and (c) HMFNs are internalized into the L929 cell after 12 and 24 h of incubation; (b) and (d) the internalized HMFNs trapped inside the cytoplasm are viewed from an enlarged rectangular area and the trapped HMFNs show the hollow structure.

Fig. 6. FT-IR spectra of the pure RFP, INH, and the drug-loaded HMFNs.

Fig. 7. (a) TG curves of HMFNs, RFP-loaded HMFNs, INH and RFP co-loaded HMFNs, (b) the magnetic hysteresis curves of HMFNs, RFP-loaded HMFNs, INH and RFP co-loaded HMFNs.

Fig. 8. Release profile of RFP and INH from INH-RFP-HMFNs in PBS at 37 °C.