Hibiscus virus in cancer therapy

HIBISCUS CHLOROTIC RINGSPOT VIRUS: This virus infects Hibiscus plants, disfiguring the flowers. A virus which affects the Hibiscus plant, giving the flower a speckled look, may prove to be a boon in clinicians' fight against cancer in human and perhaps other diseases as well. A research team led by Prof Wong Sek Man, Department of Biological Sciences, has assigned this virus a very significant role. Making it a carrier of an anti-cancer drug, Doxorubicin, they have successfully developed a novel delivery platform for drugs.

Nanotechnology has made possible the introduction of drugs embedded in polymer particles, not just into our body, but specifically to reach target sites. Virus and bacteria are also increasingly explored as more effective delivery systems compared to polymer. The virus, Hibiscus chlorotic ringspot virus is miniscule, measuring only 30 nanometres (nm) in diameter as compared to 50,000 nm, the width of a human hair. Its tiny size makes it ideal as effective nano-material for drug delivery.

PLANT VIRUSES IN DRUG DELIVERY: Prof Wong Sek Man (standing) and Mr Ren Yupeng at work in the lab. The team's paper, Folic Acid-Conjugated Protein Cages of a Plant Virus: A Novel Delivery Platform for Doxorubicin authored by Prof Wong, Mr Ren Yupeng a PhD student from the Department of Pharmacy and his supervisor, Assoc Prof Lim Lee-Yong (now teaching in Australia) was recently published online by the American Chemical Society. It will also be carried in the Society's journal, Bioconjugate Chemistry.

Said Prof Wong, whose research interests include the study and discovery of plant viruses as well as virus-resistant transgenic plants: "I started researching the Hibiscus virus way back in 1996 when there was talk about making the flower into syrup for human consumption -- like the rose syrup. The idea didn't take off but I had taken a really close look at the virus when studying ways of treating infected Hibiscus plants."

Using knowledge gleaned from past studies, the team prepared nanosized protein "cages" using the Hibiscus chlorotic ringsport virus as a model plant virus. The "cages" are capable of encapsulating the anticancer drug. Folic acid was "conjugated" onto the capsid (the protein shell that surrounds the virus) so that the capsid is able to better target cancer sites. They found that the system (in vitro using cell lines) was able to improve the uptake of Doxorubicin in ovarian cancer cancer and nasopharyngeal cancer cells. Their findings would have implications in the development of viable templates for targeted drug delivery in cancer chemotherapy.

Producing virus-resistant watermelons

In a separate study, Prof Wong Sek Man has successfully produced watermelons which are resistant to three viruses: the Cucumber mosaic virus, the Watermelon mosaic virus; and the Zucchini yellow mosaic virus. This is a joint effort with China's Shanxi Watermelon Seed Company and China Agricultural University.


RESEARCHING WATERMELONS: Prof Wong Sek Man (standing, 2nd from right) with Chinese researchers at a watermelon farm in Shanxi province of China.

Said Prof Wong: "These three viruses are the most prevalent ones infecting water melons. Infected plants will not be able to bear fruits. We took some seven years to come out with a transgenic species which will not be susceptible to these viruses."

His counterparts in China are currently applying permit to enable these transgenic water melons to be available commercially. Said team member Mr Ren Yupeng: "Unlike viruses isolated from animal origins, plant viruses are less pathogenic. Being plant viruses, they are also less likely to cause immune response in humans." Plant viral capsids also provide other advantages for drug delivery, said Yupeng. They are ideal vessels for foreign material loading. By adjusting the environmental pH and ion contents, the capsids can be disassembled (deconstructed), allowing the removal of their native viral RNA. The outer coat which forms a protein "cage" is then purified and reassembled for "cargo loading" -- in this case, the loading of the anti-cancer drug, Doxorubicin.

Prof Wong explained that the capsids on reaching target sites will burst due to them swelling under an alkaline condition (our body fluid is alkaline), hence releasing their load, the anti-cancer drug. This is a natural mechanism of plant viruses. The Cowpea chlorotic mottle virus for example, has a stable pH 5.0 but will undergo a 10 per cent radial expansion when the pH is raised. The virus particles will dissociate, releasing their viral RNA once the pH is raised above 7.5. Their findings in this area were published in an earlier paper, In vitro-reassembled plant virus-like particles for loading of polyacids carried by Journal of General Virology (2006).

Prof Wong's team is also working on obtaining the biologically active clones of Hibiscus latent Singapore virus and Zucchini yellow mosaic virus for further research in this field.