Targeted delivery of anticancer drugs exclusively to cancer cells and controlled release of the drugs in a sustained manner inside cancer cells has been achieved by a group of researchers from the Indian Institute of Science Education and Research (IISER) Kolkata. Porous carbon nanospheres about 150 nm in diameter and packed with drugs inside the pores has been designed in such a way that they cannot get inside normal cells and kill them. The results were published in the journal Carbon.
A team led by Dr. Sayan Bhattacharyya from the Department of Chemical Sciences, IISER Kolkata, used the commonly available lemon grass to synthesise the porous carbon nanospheres, which act as drug carriers. “It’s a very simple and cheap process to produce carbon nanospheres from lemon grass. Also, it is possible to scale up the production,” Dr. Bhattacharyya says.
The anticancer drug doxorubicin is covalently bound both inside the 3.6-3.8 nm diameter pores and also on the surface of the nanospheres. “Since the inside of the cancer cell is acidic (pH 5.5-6), the hydrazone covalent bond gets broken slowly to release the drug. As normal cells have a neutral pH the covalent bonds are less likely to be broken and therefore the drug cannot be released,” says Sutanu Kapri from the Department of Chemical Sciences, IISER, Kolkata, and the first author of the paper. “Also, in the presence of acidic environment, a proton gets added to the amine group of the drug and helps in the release of the drug from the pores.”
The checks and balances in targeted delivery ensures that negligible amount of cancer drug is available inside normal cells.To make the targeted delivery nearly fail-proof, the researchers attached folic acid to the nanospheres. The folic acid attaches to the folate receptors found on the surface of cancer cells and the nanospheres gain entry into cancer cells. Normal cells contain very few folate receptors and so nanospheres are nearly prevented from getting inside. Due to poor folate expression in normal cells, even after 15 hours, the amount of drug available inside normal cells was negligible compared with cancerous cells.
“The efficiency of nanospheres to get inside healthy cells will be less compared with cancerous cells. The larger the size of particles, the slimmer the chances of getting inside cells,” says Dr. Sankar Maiti from the Department of Biological Science, IISER, Kolkata, and one of the authors of the paper, while explaining how the relatively large (150 nm) nanospheres selectively target only the cancerous cells.
All these checks and balances ensure that drug release is minimal inside the healthy cells. In contrast, conventional chemotherapy is not designed to target only the cancerous cells. As a result, cancer treatment tends to kill more of healthy cells than cancerous cells.
Besides targeted delivery, the researchers had designed the nanospheres for controlled release of the anticancer drug. “Usually, there is a sudden burst of drug inside cancerous cells. But we can control the release of the drug inside cancerous cells over a 24-48-hour period, useful for clinical applications. This is mainly because the drug is chemically trapped inside the pores of the nanocarriers,” says Dr. Bhattacharyya.
Since the nanospheres contain numerous pores, the surface area increases, and a greater quantity of drug can be loaded inside the nanocarriers. Unlike when drugs are physically adsorbed on the surface of a nanocarrier, there is slim possibility of premature release of the drug into blood when the drug is bound to a nanocarrier.
Compared with freely available anticancer drug, the researchers found that the quantity of drug carried by nanospheres was 10 times more inside cancerous cells. Though nanocarriers cannot enter the nucleus, higher doses of the drug ended up inside the nucleus after 15 hours.
“So nanocarriers can effectively deliver drug in a controlled manner at targeted sites only if they have a porous structure, the drug remains inside pores and is covalently bound to nanospheres and is released only when the pH is acidic,” says Dr. Bhattacharyya.