From an old anti-cancer drug,new hope

A research team led by a Harvard scientist has found a way to significantly reduce Cisplatin's harmful effects on the kidney by creating larger nanomolecules

Written by Pupul Chatterjee | Published:July 18, 2010 11:14 pm

Cisplatin,an anti-cancer drug used in first-line chemotherapy,which,till now,could only be used in limited quantity,can now be used effectively by attaching its molecules with nano particles of platinum. The dosage of Cisplatin had to be restricted as while attacking the tumour,it also damaged the kidneys,but research has done away with this limitation.

The research team was led by Shiladitya Sengupta,a Harvard assistant professor of medicine,health sciences and technology,including scientists from National Chemical Laboratory (NCL),Pune,Transitional Health Science and Technology Institute,New Delhi,University of Notre Dame,Harvard-MIT Division of Health Sciences and Technology and Dana-Farber Cancer Institute. Sengupta’s Laboratory for Nanomedicine at Harvard-affiliated Brigham and Women’s Hospital carried out the research on Cisplatin over three years.

The drug,discovered about 40 years ago,is relatively inexpensive and effective against many cancers. Its toxicity,however,limits its use. “Even if you can see amazing results as an anti-tumour therapy,you weren’t able to give more of it,” said Sengupta. That is set to change now. Two similar drugs that use platinum are available in the market,but along with being less toxic to the kidney,they are also less active against tumours.

Cisplatin’s effectiveness and its toxicity lies in the fact that it easily releases platinum,both at the tumour site and in the kidneys. Manufacturers of the two alternative drugs have reduced drug toxicity by making them hold on to their platinum tightly. Sengupta’s work took a different track. Understanding that particles greater than five nanometres in size would not be absorbed by the kidney,he set out to engineer a super-sized Cisplatin that went on to show minimal toxicity to the kidneys.

“Cisplatin is four nanometres in diameter. Particles less than five nanometres in diameter enter the kidney. The Cisplatin-polymer complex developed by us is 80-100 nanometres in diameter. It does not enter the kidney,thus controlling the damage it earlier used to do,” said RA Mashelkar,from NCL,one of the co-authors of the study.

After studying the chemical properties of the Cisplatin molecule and its molecular folding,the team designed a polymer that would bind to Cisplatin. By stringing together enough Cisplatin,the whole molecule wrapped in a ball,100 nanometres in size,is too large to enter the kidney.

Though the initial design proved nontoxic to kidneys,it wasn’t as effective as the original Cisplatin. Sengupta and colleagues tweaked the chemical formula so the molecule didn’t hold tightly to the platinum atoms. Sengupta said,”We have demonstrated that a 3 mg/kg dose,Cisplatin is so toxic that it shrinks the kidney by half. In contrast,the nanoparticle-Cisplatin molecule has a greater effect on the tumour at the same dose but has no effect on the kidney. Cisplatin is one of the three most commonly used chemotherapies in the clinic,but since its discovery 40 years ago,limited progress has been made to improve it. Using the new development,clinicians can now carpet bomb the tumour without the kidney toxicity. This is a classical case of nanotechnology uncapping the potential of a drug that could never be optimally used before.”

Studies conducted by Basar Bilgicer,assistant professor at the University of Notre Dame,showed that the molecule accumulated in tumour tissue,whose leaky blood vessels allowed it to pass through capillaries feeding the tumour. (The molecule is too large to pass into other tissues). Once lodged in the tumour,the higher acidity there caused the molecule to fall apart,dumping its toxic load on the cancerous tissue.

The research has been tested on laboratory animals and is yet to be put to clinical trial.

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