A major problem in treating cancer is that cancer cells develop drug resistance. Scientists have been trying to find a way of killing cancer cells that have developed ‘multi-drug resistance’, or MDR.

A team of researchers from IIT-Jodhpur have reported a breakthrough, at the heart of which is the use of specially designed nanoparticles. Indeed, this breakthrough is an entirely new pathway of therapy, whose technological underpinnings can be applied in treating several other diseases, too.

The team, headed by Dr Raviraj Vankayala, took up lung cancer for their study.

Now, how to kill cancer cells? One good way is to oxidise them. Cancer cells, like all cells, die if they accumulate oxygen. Accumulation of oxygen happens when any molecule containing oxygen gets into the cell. Such oxygen-containing molecules that damage cells are called ‘reactive oxidative species’ or ROS, better known as ‘free radicals’. The oxygen in the ROS reacts with the many chemicals in the cells, destroying their functions, effectively killing them. This is called ‘oxidative stress’. Doctors routinely advise us to take antioxidants, such as fruits. The purpose of antioxidants is to remove ROS.

The right receptor

All cells, including cancer cells, naturally have defence mechanisms against ROS. Now, the trick to kill cancer cells is to quell its defence mechanism. Defenceless, the cells get oxidised and die.

The next question is, how to demolish the cancer cell’s anti-oxidative defence mechanism. Here is where IIT-Jodhpur’s research comes in. The team developed a special type of nanomaterial called ‘upconversion nanoparticles’, or UCNP, which is a cocktail of rare metals. A useful property of UCNP is that when they absorb light (get energised) they produce so much ROS as to overwhelm the cell’s antioxidant defence mechanism. Think of them as Popeye after eating a can of spinach!

Cast of characters
1. UCNP, or ‘upconversion nanoparticles’, is a cocktail of rare metals that produce ROS, or ‘reactive oxidative species’, under infrared, visible or ultraviolet light
2. ROS, also known as free radicals, are molecules containing oxygen that can enter cells. ROS are harmful
3. EGFR, or ‘epidermal growth factor receptors’, are found on the surface of lung cancer cells. Receptors are the entry points of a cell
4. Anti-EGFR antibodies are proteins that can bind to EGF receptors
How it works
1. UCNP binds with anti-EGFR antibodies to form modified UCNP
2. The modified UCNP, led by anti-EGFR antibody, enters cancer cells through the EGF receptors
3. When infrared light is shone on UCNP, it produces lots of ROS
4. ROS creates oxidative stress in cancer cells, overwhelming their anti-oxidant mechanism to kill them

The next step is to get the UCNP into cancer cells — and, again, only into cancer cells and not healthy cells. To do this, Vankayala’s team zeroed in on a specific feature of lung cancer cells, called ‘epidermal growth factor receptor’, or EGFR. These receptors are a sort of entry point into a cell. In the case of the SARS-CoV-2 virus causing the Covid-19 pandemic, for instance, the spike proteins of the virus bind to the ‘ACE2 receptor’ in human cells to enter them. The EGFR are similar receptors that are overproduced in lung cancer cells.

Vankayala’s idea was to modify the UCNP to home in on the receptors in lung cancer cells (and not healthy cells). The team hit upon an ingenious ploy for this. They attached the UCNP to a commercially available anti-EGFR antibody. The UCNP has a carboxyl group, the anti-EGFR antibody has an amine group. The carboxyl and amine join hands, and you have a molecule that can enter the lung cancer cell through the EGF receptor. In a way, the anti-EGFR antibody leads the UCNP inside the cancer cells. All you need to do now is shine an infrared light on the cancer cells. Nourished with IR, the UCNP produces copious quantities of ROS, creates oxidative stress in the cancer cells and kills them.

Challenges

While this treatment pathway has been proven in a lab, there are still some challenges in its practical application, Vankayala says. For example, it is important to ascertain that UCNP does not prove to be toxic or have other deleterious side-effects.

Another challenge is the need to produce UCNP in large quantities. While testing in mice a few milligrams are enough, but you’d need several grams to test on a human. However, these are not insurmountable problems.

Once validated in clinical trials, which would take at least a few years, this can prove to be a cure for cancer. IIT-Jodhpur experimented with lung cancer cells, but for other types of cancer, it is just a question of finding other nanoparticles similar to UCNP.

The UCNP method can also be used in diagnosis. The nanoparticles glow when lit with IR — they can be a good biomarker to identify bad cells. This opens up a completely new field of diagnosis. Vankayala calls it ‘nano-theranostics’.

Indeed, this treatment pathway could be extended to many diseases. Vankayala says that neuro-degenerative disorders can be the first of the other candidates. In fact, the pathway has potential to completely revolutionise the field of medicine itself. “But that would take a decade or two,” cautions Vankayala.

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