Tuberculosis
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Nanotechnology in medicine

Nanotechnology is manipulation of matter conducted on the nanoscale, which is at the level of atoms and molecules. It has shown great benefit across a range of industries, from manufacturing to food production. There is also an increasing presence of nanotechnology in medicine, where it offers particularly exciting possibilities and has the potential to revolutionize the way diseases and disorders are diagnosed and treated1.

The use of nanotechnology in the development of drug delivery systems has been particularly well explored. Nanoparticles have been used to reduce the toxicity of cancer treatments by specifically delivering chemotherapy agents or heat to target cells types. This ensures that the cytotoxic effects are localised to the tumour, and so are not widely detrimental to healthy tissue and fewer side effects are experienced.

Nanoparticles are also used as diagnostic imaging agents. For example, magnetic nanoparticles such as Gd3+, Mn2+, Fe3+ act as contrast agents for magnetic resonance imaging (MRI). The addition of paramagnetic cations (usually iron for minimal toxicity) to a drug delivery system thus allows drug distribution to be visualised non-invasively.

The incorporation of diagnostic and therapeutic functions in a single nanoparticle is known as theranostics2. This integrated approach holds great potential for personalized medicine as drug availability at the target site can be monitored for each individual patient and the dose adjusted to achieve optimal efficacy.

Metal-organic frameworks (MOFs) are promising new candidates for targeted drug delivery as they have good biocompatibility and biodegradability whilst having a high capacity for carrying drug. Furthermore, they offer the potential for controlling drug release profiles through the choice of functional group used for the linker and by adjusting the pore size. In addition, the ion core of MOFs serves as a contrast agent for MRI making them potential agents for theranostics3.

The development of theranostics has been focussed largely on cancer therapies, but there is a wide range of other indications that could benefit from targeted and traceable drug delivery. In particular, delivery of sufficient antibiotic to infected areas of the lung is critical for effective treatment of tuberculosis (TB).

Tuberculosis

TB is infection with the bacteria Mycobacterium tuberculosis complex. It commonly affects the lung, but the infection can spread via blood to other organs in the body. TB is transmitted by inhalation of airborne bacteria exhaled by an infected individual. It is one of the top three infectious diseases causing morbidity and death worldwide. There are in the order of 10 million new cases each year and about 2 million deaths from TB annually.

TB can be effectively treated with a 6‑9 month course of antibiotics. There are, however, several barriers to successful treatment. The concentrations of drug reaching the lungs is unpredictable and often does not reach therapeutic concentrations. In particular, it has been reported that drugs levels are markedly lower in infected lung tissue than in the surrounding tissue. Oral administration results in peaks and troughs in drug concentration and, as a result of drug levels commonly falling below the effective dose, multidrug-resistant forms of TB are becoming increasingly common. Furthermore, unacceptable toxicity from the effective drugs available often requires early discontinuation of antibiotic treatment.

One of the most effective treatments for TB infections is isonicotinic acid hydrazide (INH), but it is associated with several serious side effects4. A theranostic carrier that could deliver INH to TB-infected tissue with minimal toxicity to healthy cells and allow easy determination of drug distribution would thus be highly desirable in the treatment of TB.

In addition, pulmonary administration would deliver drug directly to the infected macrophages in the deepest part of lungs and ensure high local drug concentrations. Development of an inhaled dry powder TB therapy is considered to be the most promising strategy for improving TB treatment and achieving global TB control.

Theranostics in the treatment of TB

An iron MOF (Fe-MIL-101-NH2) has recently been developed as a theranostic carrier of INH5. Its potential as an MRI contrast agent were evaluated using Bruker's 9.4 T MRI research system and TopSpin 2.0 software.

The iron MOF was 3.37-6.45 μm in diameter depending on the micronization method used and displayed extended release of INH. The nanoparticles were detected in the fibroblast cytoplasmic area indicating that INH would be released inside the cells. It was also confirmed that the proposed drug delivery system could also serve as an MRI contrast agent. In vitro cytotoxicity studies showed the iron MOF to be safe.

MRI imaging in this way has identified that the Fe-MIL-101-NH2 nanoparticles represent a promising novel strategy for the delivery of TB therapeutic agents and the monitoring of their distribution within lung tissue. It is hoped that this INH-carrying MOF can be developed into an inhalable treatment for TB.

References

1. Formoso P, et al. Nanotechnology for the environment and medicine. Mini-Rev Med Chem. 2016;16(8):668-75.

2. Ahmed N, et al. Theranostic applications of nanoparticles in cancer. Drug Discov Today. 2012;17(17-18):928-34.

3. Horcajada P, et al. Porous metal-organic-framework nanoscale carriers as a potential platform for drug delivery and imaging. Nat Mater. 2010;9(2):172-8.

4. Kaur M, et al. A Review of emerging trends in the treatment of tuberculosis. Artif Cells Nanomed Biotechnol. 2014;44(2):478-84.

5. Wyszogrodzka G, et al. Iron-Based Metal-Organic Frameworks as a Theranostic Carrier for Local Tuberculosis Therapy. Pharm Res 2018;35:144‑155.