Tomorrow's Health, Today's Research

Devika Chithrani

Assistant Professor, Department of Physics and Astronomy
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Phone: 250-721-7702
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Research Area: Medical physics, synthesis and characterization of nanoparticles, development of nanoparticle based systems for multimodal imaging and therapeutics, nanoparticle based radiosensitizers, drug delivery, intracellular fate of nanoparticles.
 
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Research Profile:

A Tiny Trojan Horse: Using gold nanoparticles to deliver anti-cancer drugs to tumour cells enhancing radiation and chemotherapy


 The human body is made up of trillions of cells between 15 and 70 trillion and within each one of these cells, an immeasurable number of things can go wrong. One of these things is cancer. 

Cancer, the uncontrolled division of abnormal cells within the human body, is newly diagnosed over 10 million times each year across the globe. While treatment modalities such as chemotherapy and radiation exist, there are still immense challenges to be overcome in order to improve efficacy and reduce side effects. 

Luckily Dr. Devika Chithrani, a UVic professor specializing in medical physics and a leading researcher in the use of gold nanoparticles in cancer imaging and treatment, isn’t one to give up easily when faced with a challenge. 

When Chithrani couldn’t find a PhD supervisor in UToronto’s Department of Physics she was told that her intention to capture photons from a single quantum dot located on a nano-template was akin to a 15 year project, rather than a PhD thesis she simply left and found one in the Material Sciences and Engineering Department. 

Three years later, Chithrani presented her thesis in a very short and sweet defense, detailing the experimental evidence and quantum theory behind a single artificial atom.

 “This is the difference between me and most other people,” says Chithrani. “When people say, ‘You cannot do it,’ I get motivated. It drives me.” 

Chithrani has certainly heard more than her fair share of doubt. “I loved science as a child,” says Chithrani. “I decided to go into physics. Most of the students were boys and they said I shouldn’t be in that program. They asked me to leave.” So Chithrani stayed and upon her graduation from the University of Colombo was awarded the gold medal, not just for physics, but for the entire science faculty. 

Nanotechnology and cancer. After earning an MSc in Condensed Matter Physics and a PhD in Quantum Physics, Chithrani set her sights on improving the interface between nanotechnology and medicine during her post-doctoral research. 

Currently, as the director of UVic’s Nanoscience and Technology Development Laboratory, Chithrani conducts research into novel medical applications, working to develop smart nanomaterials to improve existing cancer therapies. 

Drug delivery. When it comes to chemotherapy, designing anti-cancer drugs is only half the battle. The other half is getting them to the right spot. Human cells are highly complex and dynamic environments that have a high degree of control over what they allow in and out. While advantageous when it comes to noxious foreign substances, this makes targeted drug delivery difficult for medical researchers. 

One novel approach to this problem includes the use of nanoparticle delivery complexes. Essentially tiny molecular taxis designed to safely transport drugs across membrane-barrier checkpoints to a specific destination malignant tumour cells. 

“People want to figure out how to use nanoparticles to deliver drugs and improve imaging. So, how do we get nanoparticles into these cells?” asks Chithrani. 

Gold nanoparticles (GNPs). In order to answer this question, Chithrani is studying the uptake of gold nanoparticles (GNPs) in mammalian cells. Gold is an advantageous choice for medical applications in several ways. It is nontoxic. It has a high Z number. It is the right size. 

GNPs can be assembled into complex’s that range between 10nm and 100nm in diameter, not coincidentally the same size as many naturally occurring entities that are capable of crossing the cell membrane. 

“If I am to learn something,” says Chithrani, “it is from nature. What do we eat? Proteins. They are within this range. How do we get sick? Viruses. They are within this range.” 

GNP size and shape. Chithrani’s monocellular studies have shown that the kinetics and saturation concentration of GNPs within cells is highly dependant upon the physical dimensions of the GNP, with a maximum uptake of GNPs in the 50nm range. 

Following her single-cell study, Chithrani created a 3-dimensional, multilayered cell culture model in order to study the uptake and distribution of GNPs in a microenvironment that is more representative of a real, solid tumour. By analyzing intracellular and extracellular particle distribution, Chithrani has shown that GNPs smaller than 50nm in diameter, surprisingly, achieved the highest rate of intracellular uptake. The increased uptake of smaller GNPs in solid tumours is most likely due to their ability to squeeze through small channels in the matrix, channels that are actually formed by excretions from the tumor itself. 

These experiments translate into valuable information when it comes to designing NPs for drug delivery, where factors such as control over intracellular delivery rate and concentration are imperative. 

Peptide-modified GNPs. Chithrani is also studying peptide-modified GNPs as a way of improving cellular uptake, nuclear transport, and intracellular retention. Specifically, targeting the nucleus headquarters to the faulty genetic material may enhance the therapeutic response. 

Chithrani’s studies showed a promising five-fold increase in GNP uptake into the cell nucleus with the addition of three functionalized peptides: RGD-peptide, to enhance uptake; NLS-peptide, to facilitate nuclear delivery; and pentapeptide, to prevent serum-protein binding to the NP surface leading to exocytosis. 

In vivo/animal studies. Chithrani recently completed a successful in vivo study of modified GNPs on pancreatic tumours in mice, in which 10 to 12% of the injected gold was able to reach the tumour. 

“I actually decorate my gold,” says Chithrani. “It’s not just bare gold. We put certain molecules on it.” 

What kind of “decorative” molecules does Chithrani use to enhance her GNPs? Molecules such as: PEG, which prevents GNP-uptake by macrophages before they reach their intended destination; along with other peptides that help GNPs gain entrance to the cells by binding to specific membrane receptors. 

While it varies from cell to cell, a single tumour cell can house between 6,000 and 10,000 GNPs. The rest of the gold is either excreted or taken up by other organs, such as the liver and spleen, which doesn’t pose much of a problem because gold is not a very toxic element. In fact, it has been used for centuries to treat arthritis.

Radiation and GNPs. Through her research, Chithrani has also been able to show for the first time that GNPs can be used as a radiation dose enhancer at clinically relevant MV energies.

 “90% of our body is water,” says Chithrani. “When you radiate a person, the radiation interacts with materials, especially the water, and this creates free radicals that damage our DNA, effectively killing the undesirable tumor cells.” 

Because of its high atomic number, gold, in the presence of radiation, actually creates even more free radicals, essentially enhancing the dose of radiation to the GNP-filled cells that lie in the path of the radiation beam. This means that the overall dose of radiation could theoretically be lowered, reducing unwanted side effects stemming from unintentional harm to healthy neighbouring cells. 

Collaborative work. In addition to her work at UVic and BCCA-Vancouver Island, Chithrani has several joint projects in progress and collaborates with a host of researchers from institutions that include: MD Anderson Cancer Centre, Harvard Medical School, NortheasternU, UToronto, and Toronto Medical Discovery Tower, as well as numerous other universities and cancer centers. 

“We don’t work on the same things,” explains Chithrani. “I go this way, they go that way, and then we share. This increases our scope.” Always the physicist, Chithrani describes these collaborative relationships as “entanglement.” 

Teaching. While research and academic writing consume much of Chithrani’s life, she is always able to find time for her students. “It’s not a job,” says Chithrani, who is a dedicated assistant professor with UVic’s Department of Physics and Astronomy. “I never consider this a job. I think it’s a privilege to work with young people.”