14 DAY TRIAL // The advantage of using nanoparticles to deliver strong cancer drugs, is that not only it improves efficiency, it also limits the negative side effects of the treatment, a new research carried out by scientists at MIT and Brigham and Women’s Hospital concluded.
The cancer drug in question is cisplatin, and even though the drug causes adverse side effects like nausea and kidney and nerve damage and it also has a very short life in the bloodstream, nearly half of all cancer patients receiving chemotherapy are taking it, or other platinum drugs.
The difference with the new nanoparticle is that it delivers the drug in a form activated when it reaches its target, increasing efficiency and decreasing the necessary dosage.
In their experiment, the researchers showed that cisplatin was delivered more efficiently and safely in a form encapsulated in a nanoparticle targeted to prostate tumor cells.
In mice, the tumors shrank after using one third of the conventional amount of drug necessary to achieve the same effect.
Cisplatin started to be used back in the 70s, since it destroys cancer cells by cross-linking their DNA, thus triggering cell death.
The problem was that only 1% of the dose given to a patient actually reached the tumor cells' DNA, and nearly half of it is eliminated from the body within an hour of treatment, so researchers had to find a viable alternative.
So, in order to extend the time in circulation, they decided to introduce a derivative of the drug in a hydrophobic nanoparticle.
Before doing so, they had to modify the drug since it is normally hydrophilic, so they added two hexanoic acid units (water-repelling organic fragments) that encapsulates the resulting prodrug (a compound that's inactive before it reaches its target) in a nanoparticle.
This approach allow a higher quantity of the drug to be delivered to the tumor, since it limits the degradation of the drug within the bloodstream.
The result – the nanoparticles circulated in the bloodstream for 24 hours, which is five times longer that un-encapsulated cisplatin, and the drug did not accumulate as much in the kidneys.
But how do nanoparticles know where is their target and how to reach it?
To help them out, the researchers coated them with molecules that bind to PSMA (prostate specific membrane antigen), a protein found on most prostate cancer cells.
Once the nanoparticles proved their durability in the bloodstream, the researchers tested them in mice with implanted human prostate tumors, and found that they reduced tumor size as much as the conventional drug did in 30 days, except that this time only 30% of the dosage was necessary.
The anti-cancer research evolves every day – in 2008, scientists proved that nanoparticles worked in cancer cells grown in a lab dish, and since now, they have shown promise in animal models, the team hopes to move on to clinical trials in humans very soon.
Stephen Lippard, the Arthur Amos Noyes Professor of Chemistry and a senior author of the paper published on this matter, says that “at each stage, it’s possible there will be new roadblocks that will come up, but you just keep trying.”
Mansoor Amiji, chair of pharmaceutical sciences at Northeastern University’s Bouvé College of Health Sciences, who was not involved in the research, added that “they have very elegantly showed not just improved efficacy but also decreased toxicity.
“With a nanoparticle, you should be able to get higher doses into the patient, so you can have a much better therapeutic result and not worry as much about side effects.”
This type of nanoparticle design could easily be used for other types of drugs, and even more than one drug at a time, and also be used to target other tumors, as long as they have known receptors that can be targeted, the researchers said.
Another senior author on the paper is Omid Farokhzad, associate professor at Harvard Medical School and director of the Laboratory of Nanomedicine and Biomaterials at Brigham and Women’s Hospital.
He says that additional animal testing is needed before the cisplatin-carrying particles can go into human clinical trials, but adds that “at the end of the day, if the development results are all promising, then we would hope to put something like this in humans within the next three years.”
Shanta Dhar, a postdoctoral associate in Lippard’s lab, and Nagesh Kolishetti, a postdoctoral associate in Farokhzad’s lab, are co-lead authors of the paper that appears in the Proceedings of the National Academy of Sciences this week.