Novel Drug Delivery System To Kill Cancer Cells
Researchers at the Indian Institute of Science Education and Research (IISER) Pune have successfully developed a novel cancer drug delivery system using graphene oxide nanoparticles. In a serendipitous discovery, a team led by Dr. Sudipta Basu and Dr. Nirmalya Bhallav from the Department of Chemistry found that when a FDA-approved anticancer drug cisplatin was added, the graphene oxide sheets self-assembled into spherical nanoparticles enclosing the drug within.
(From left) Aditi Nandi, Dr. Sudipta Basu and Dr. Nirmalya Bhallav found the drugs were being released in a slow and sustained manner inside the lysosomes and killed the cancer cells predominantly through programmed cell death.
“We were very surprised to see this kind of shape-shifting transformation of the graphene oxide sheets into a spherical structure. We are exploring the mechanism by which this happens,” says Dr. Basu, the corresponding author of the paper. “We think the drug is reacting with graphene oxide and transforming the graphene sheet into a ball-like structure, a kind of ‘molecular stitching’,” adds Dr. Ballav.
Two DNA-damaging anticancer drugs — proflavine and doxorubicin — that bind to graphene oxide through non-covalent bond were also used. “These two drugs have no role in changing the morphology [shape] of graphene oxide from a sheet to a spherical nanoparticle,” says Aditi Nandi, doctoral student at the Department of Chemistry, IISER Pune and the first author of the paper.
In the lab, the nanoparticles of 90-120 nanometre size containing cisplatin and either of the two anticancer drugs were taken up by cervical cancer cells leading to programmed cell death. The results were published in the journal Chemical Communication.
“The nanoparticle containing cisplatin alone was able to kill cancer cells. But there is additive effect when two drugs are used together and efficiency of killing the cancer cells becomes better,” says Dr. Basu. The drugs bind to the DNA strands and break the strands so cell division does not happen and programmed cell death ensues.
The cisplatin nanoparticles containing either proflavine or doxorubicin were found to get into the lysosomes of a cell in a time-dependent manner. Once inside the lysosomes, the drugs were released in a slow and sustained manner and killed the cancer cells predominantly through programmed cell death.
In the case cisplatin nanoparticles containing proflavine, about 54% of proflavine was released in about 2 days while 22% of cisplatin was released after three days. For cisplatin nanoparticles containing doxorubicin, more (33%) of cisplatin and less (22%) of doxorubicin was released after three days. “Slow release of the drugs is better as the drugs will be effective for a longer period of time,” says Dr. Basu. The nanoparticles containing the drugs targeted only the cancer cells.
Though the study found that comparable concentration of doxorubicin and proflavine was required to kill 50% of the cells at the end of 48 hours, Dr. Basu prefers to use doxorubicin. “Both cisplatin and doxorubicin are FDA approved drugs, while proflavine is still undergoing animal trials. So we prefer to use the already approved drugs,” he says.
“It is interesting that graphene oxide, a cheaply abundant carbon-based material, can be used for various applications ranging from material science to biomedical research,” says Dr. Ballav.
Interestingly, once cisplatin is released inside the cell, the spherical nanoparticle loses its shape and once again regains its original sheet-like structure. “We expected to see graphene change its shape from a sphere to sheet-like structure once cisplatin is released. We confirmed this using scanning electron microscopy,” says Ms. Nandi.
The researchers are planning to undertake more studies using other cancer cells and eventually use animal models. “We anticipate the graphene oxide-based nano platform will be useful for next-generation cancer therapy, specifically targeting the mitochondria,” Dr. Basu says.