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LITTLE MAGNETIC MICROORGANISMS TREATING DEADLY BRAIN TUMOR: A NANO TARGETED THERAPY

Ankita Rathore and Biju Dharmapalan

E-mail: biju@macfast.org

 

Are you aware that there exist little magnetotactic bacteria on earth surface with built in compasses, just like a magnet, to keep a track of earth’s magnetic field? This has intrigued the scientific community over a past few years leading to many exciting scientific discoveries- treating Glioblastoma Multiforme through nano targeted therapy is one such discovery, as you will learn soon.  

Magnetotactic Bacteria, Magnetosomes & their magnetic personality

Magnetotactic bacteria (MTB) are a diverse group of microorganisms with the ability to orient and migrate along geomagnetic field lines. This unique feat is based on specific intracellular organelles, the magnetosomes, which, in most MTB, comprise nanometer-sized, membrane bound crystals of magnetic iron minerals and organized into chains via a dedicated cytoskeleton. Because of the special properties of the magnetosomes, MTB are of great interest for paleomagnetism, environmental magnetism, biomarkers in rocks, magnetic materials and biomineralization in organisms, and bacterial magnetites have been exploited for a variety of applications in modern biological and medical sciences.

The history of magnetotactic bacteria goes long back to 1960s, when Richard Blakemore discovered them. They consume iron salts and biomineralize them into magnetite (Iron Oxide) or greigite (Iron Sulphide) crystals in bacterial entities known as Magnetosomes. These nano-crystals of size around ~50 nm provide these magnetotactic bacteria their natural magnetism. However, these bacteria are unable to survive in aerobic (too much oxygen) or anaerobic (no oxygen) conditions and only thrive in ‘micro-aerophilic’ (a perfect oxygen controlled) environment in sediment or water bodies. Perhaps in the quest of ideal oxygen environment, they have evolved a magnetic process called ‘magnetic-aerotaxis’ to adequately utilize Earth’s magnetic field. With the help of this, intracellular nanocrystal chains of magnetite or greigite in magnetosomes align themselves according to Earth’s natural magnetic field.

 

The discovery of these magnetotactic bacteria evoked a great scientific interest in magnetosomes and its potential applications in the field of medicine. The various applications are medical imaging (MRI), targeted drug delivery, gene research and tumor hyperthermia. The most fascinating of them all is hyperthermia in which there is controlled heating of magnetic nanoparticles (magnetosomes) on exposure to alternating magnetic field (AMF) to promote necrosis of tumor cells. This is just the time to use these magnetosomes as magnetic nanoparticles in Magnetic hyperthermia-mediated cancer therapy (MCHT) for treatment of Glioblastoma multiforme (GBM), a deadly brain tumor.

Glioblastoma: the deadly brain tumor

Glioblastoma multiforme or GBM is most aggressive of all the gliomas, the kind which inspires fear due its infiltrative and invasive malignant nature. Imagine if brain tumors were sharks, can you guess what would Glioblastoma multiforme or GBM be? Probably, bull sharks or Great Whites!

So, what is Glioblastoma multiforme? This deadly tumor or glioma is a Grade IV tumor, which means most malignant of all arising de novo without any grade precursor. This tumor arises from brain cells called glial cells or their precursors within central nervous system. These tumors have got significant attention in scientific world as the survival rate of patients suffering from Glioblastoma is less than a year. The global incidence of Glioblastoma multiforme is less than 10 per 100,000 people making this a rare tumor but it’s poor prognosis with survival rate of approximately a year after diagnosis makes it a crucial public health issue. It is more common in males than females and also occur mostly in adults when compared to children. GBM is diagnosed at old age with median age to be 64 at the time of diagnosis.

 

The traditional treatment of such tumors involve surgery in combination with radiation therapy and chemotherapy, where drug Temozolomide (TMZ) accelerates the treatment process. Moreover, this notorious tumor have evaded the several attempts of innovative therapies due to its recurrent and malignant nature. However, scientific research has explored microRNA, gene therapy, virotherapy and intranasal therapy to find treatment of GBM and the current area of research interest is nano targeted drug delivery using magnetosomes which can cross blood brain barrier (BBB) to reach this notorious tumor.   

Tale of hyperthermia mediated nano targeted therapy

Hyperthermia, the mild elevation of temperature to 40–43°C, can induce cancer cell death and enhance the effects of radiotherapy and chemotherapy. However, achievement of its full potential as a clinically relevant treatment modality has been restricted by its inability to effectively and preferentially heat malignant cells. The limited spatial resolution may be circumvented by the intravenous administration of cancer-targeting magnetic nanoparticles that accumulate in the tumor, followed by the application of an alternating magnetic field to raise the temperature of the nanoparticles located in the tumor tissue. This targeted approach enables preferential heating of malignant cancer cells whilst sparing the surrounding normal tissue, potentially improving the effectiveness and safety of hyperthermia. 

The natural magnetic nanoparticles extracted from magnetotactic bacteria, mainly Magnetospirillum magneticum or Magnetospirillum gryphiswaldense, are known as magnetosomes. These magnetosomes have been widely accepted in scientific community for their magnetic properties, low toxicity during interaction with living tissue and thermal efficiency. These qualities of magnetosomes were impressive and this led to their usage in Magnetic Fluid Hyperthermia (MFH). Hyperthermia is an application where malignant diseases are treated by administration of heat, whereas Magnetic Fluid Hyperthermia (MFH) delivers thermal energy to the target tumor cells by exposing magnetic nanoparticles (magnetosomes) to alternating magnetic field (AMF). You must be wondering how it is done? Well, magnetosomes are injected into the tumor cells and AMF is applied, leading to rise of tumor temperature resulting selective thermal omission of tumor cells without harming neighbouring healthy cells.

Many successful studies have been done where chains of magnetosomes were used to treat experimental models of breast cancer. A recent shift is observed in research world towards the use of chains of magnetosomes to treat experimental models of glioma and it’s theranostic properties. A recent study done by a research group in Italy reports the same. Moreover, they have found these extracted chains of magnetosome to be biocompatible when tested in cell cultures, and heating therapy was also successfully evaluated in xenograft murine model of glioblastoma.  Despite promising results in preclinical studies, there are numerous challenges that must be addressed before this technique can progress to the clinic.

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