Encapsulation of Anti-Tuberculosis Drugs within Mesoporous Silica and Intracellular Antibacterial Activities

Abstract

Tuberculosis is a major problem in public health. While new effective treatments to combat the disease are currently under development, they tend suffer from poor solubility often resulting in low and/or inconsistent oral bioavailability. Mesoporous materials are here investigated in an in vitro intracellular assay, for the effective delivery of compound PA-824; a poorly soluble bactericidal agent being developed against Tuberculosis (TB). Mesoporous materials enhance the solubility of PA-824; however, this is not translated into a higher antibacterial activity in TB-infected macrophages after 5 days of incubation, where similar values are obtained. The lack of improved activity may be due to insufficient release of the drug from the mesopores in the context of the cellular environment. However, these results show promising data for the use of mesoporous particles in the context of oral delivery with expected improvements in bioavailability.

Keywords: formulation; intracellular; mesoporous materials; nanomedicine; solubility; tuberculosis.

Figure 1

Molecular structure of (a) PA-824 and (b) moxifloxacin; (c) scanning and (d) transmission electron microscopy images of typical particles of calcined AMS-6.

Scheme I

Scheme of the experimental design, silica particles loaded with PA-824 or moxifloxacin are presented to infected macrophages for the evaluation of the antibacterial activity of the free drug and encapsulated drug.

Figure 2

X-ray diffraction patterns of (a) free moxifloxacin, and AMS-6-Moxi; (b) free PA-824, and AMS-6-PA824. Both show that the free drug in its crystalline state and the encapsulated material contains drug in the amorphous state; (c) differential scanning calorimetry (DSC) curves of free and loaded PA-824; (d) pore size distribution of calcined AMS-6, AMS-6-PA824, and AMS-6-Moxi obtained from density functional theory (DFT).

Figure 3

Kinetic release curves of (a) free and encapsulated moxifloxacin and (b) PA-824; in phosphate buffered saline buffer (PBS buffer, 10 mg/L).

Figure 4

Antibacterial activity percentage of (a) PA-824; (b) moxifloxacin; (c) AMS-6-PA824; and (d) AMS-6-Moxi. Total macrophages number after present them to drugs in different concentrations: (e) PA-824; (f) moxifloxacin; (g) AMS-6-PA824; and (h) AMS-6-Moxi (Concentration in logarithm scale).

Figure 5

Confocal microscopy images of intracellular growth of tubercle bacilli inside macrophages under the treatment of PA-824, moxifloxacin, encapsulated PA-824, and encapsulate moxifloxacin at different drug concentration. Green-bacteria with green fluorescence; Red-alive macrophages.