| Precise target: Rajkumar Banerjee along with a co-researcher in the lab
Biochemist Rajkumar Banerjee has been engaged in a bit of a target practice, a game that may change the way doctors fight human breast cancer. His bullets are tiny microscopic bubbles made of fatty molecules and watery interiors. His targets are breast cancer cells lying at the bottom of a flask containing a broth of chemicals that provide nourishment, facilitating immortality of the cells.
The bubbles called liposomes are especially designed to seek out breast cancer cells. If, as Banerjee hopes, the liposomes are eventually used in a patient with breast cancer, they will evade the destructive assaults of the human immune system, avoid the myriad other cells that make up normal tissues in the body and, like guided missiles, make their way to the breast cancer cells.
But all that's in the future. For the moment, Banerjee is working with cells in a laboratory flask, chasing a decades-old quest in medicine: targeted delivery of treatment exclusively to cancer cells. 'The liposomes are vehicles that can carry anti-cancer drugs or anti-cancer genes to the breast cancer cells,' says Banerjee, a scientist at the Indian Institute of Chemical Technology (IICT), Hyderabad.
His latest studies show that the trick in achieving targeted-attack with liposomes lies in picking the right combination of ingredients that go into building those bubbles.
In a paper accepted for publication in the Journal of Biological Chemistry, Banerjee and his colleagues from the IICT and the Centre for Cellular and Molecular Biology (CCMB) in Hyderabad have reported creating a liposome with an affinity for breast cancer cells. The researchers created the breast cancer cell-seeking liposome by chemically gluing a set of fatty molecules with a drug called haloperidol.
Haloperidol is a synthetic anti-psychotic drug that has been known for many years and used in the treatment of neurological disorders. Studies aimed at investigating its biological effect have shown that it has an affinity for proteins called sigma receptors found on neurons, or brain cells. The Hyderabad scientists exploited haloperidol's affinity for sigma receptors in making their liposome.
The sigma receptors are also found on normal cells of the liver, kidneys, lungs, and ovaries, among other organs. But they are overexpressed, or found in high amounts, in certain cancers such as that of the breast. Scientists still do not understand the link, if any, between sigma receptors and cancer. But they believe that the abundance of these proteins in cancer cells may allow them to target specific tumours.
Banerjee and his colleagues made a liposome bubble containing haloperidol and a test gene intended for delivery into the breast cancer cells. They also used a special substance called polyethylene glycol, or PEG, to impart a 'stealth property' to the liposome and help it evade the reticuloendothilial system (RES), the body's natural scavenging mechanism to mop up 'foreign' particles.
'The PEG helps the liposome escape the scavenging mechanism,' says Banerjee. The haloperidol's affinity for the sigma receptors guides the liposomes to breast cancer cells which overexpress these receptors. The interaction between haloperidol and the sigma receptors on the breast cancer cells, it is presumed, opens up a gateway for the entry of the liposomes into the cells.
The researchers tweaked the concentration of haloperidol in the liposome to get it to interact selectively with cells that overexpress sigma receptors and not with the cells with normal levels of sigma receptors. The abundance of the sigma receptors on the breast cancer cells may be 10 times higher than their abundance on normal cells in the body, says Banerjee.
In a series of experiments, the IICT researchers have shown that the liposome glued to haloperidol can deliver a test gene into breast cancer cells that overexpress sigma receptors. 'Gene therapy has long been viewed as an option in the treatment of cancer,' says Banerjee. 'But the search for an efficient techique to deliver the right genes exclusively into cancer cells is still under way.'
Elsewhere, researchers have been studying several ways to use gene therapy against cancer. One strategy aims at replacing 'bad' genes associated with cancer with healthy genes. Mutations in a gene called P53, for instance, may lead to cancer. Some researchers believe that introducing a healthy version of the gene will stop cancer cells from dividing endlessly.
Another gene therapy option under consideration is to inject cancer cells with a gene that can coax the cancer cells commit suicide. An independent scientist familiar with the IICT-CCMB work says that it 'may represent a major advancement' in gene- or drug-delivery methods.
Cancers of the colon, lung, and prostate also show higher than normal levels of the sigma receptors. So, the researchers say in their paper, such a gene delivery system may become a 'novel class of therapeutics for the treatment of human cancers.' In their laboratory, Banerjee and his colleagues have begun testing the liposomes on mice with breast cancers.