Advances in biotechnology are getting new drugs on the market more rapidly than ever, but pharmaceutical companies and researchers are increasingly realising that getting them into patients efficiently is a daunting task.

Unlike conventional medicines, most new-age drugs are biomolecules like peptides and proteins. If they were taken as a pill, they would never make to their destination as enzymes in the stomach would have easily broken them down. Similarly, almost all cancer drugs tend to be highly toxic to healthy as well as malignant cells. The best way to spare healthy tissues is to take these drugs directly to the tumour.

A study by consulting firm Frost & Sullivan two years ago said that advances in drug delivery systems are also expected to offer a host of additional advantages such as ease of administration, decreased side effects and cost reduction. “There is now a growing realisation that innovative delivery of drugs would not only increase safety and efficacy levels but also improve the overall performance of the drug,” it said.

It’s in this context that a recent achievement is significant. A team of Indian and Israeli researchers have created a nano-sized courier that may help deliver drugs right inside the cell, by mimicking one of the cell’s most efficient cargo services.

The targeted delivery system that scientists at the Indian Institute of Technology (IIT) Kanpur and at Tel Aviv University in Israel have jointly developed seeks to ape what clathrin — a wonder protein that moves a range of important molecules into the cell — does. The scientists reported their work in today’s issue of the German journal Angewandte Chemie.

Clathrin has a unique three-legged pin wheel structure known as triskelion. Each leg has a “knee” where the molecule bends and a “foot” that helps in lattice formation. This rather unusual shape makes it possible for clathrin molecules to come together and make a soccer ball-shaped polyhedral lattice with a hollow interior. Clathrin thus plays a major role in the creation of vesicles (transport packages that cross cellular membranes).

How clathrin exactly functions was unravelled by a team of international scientists from Italy, the UK and the US led by Thomas Kirchhausen of Harvard Medical School, Boston, about nine years ago.

“Clathrin molecules entrap smaller biomolecules and transport them. They thus act as a natural transporter which accepts a host of diverse molecules for delivery,” explains Sandeep Verma, an organic chemist at IIT who led the Indian team in the study.

Many clathrin molecules assemble together at incredible speed to form a tiny cage, stay together as long as it is required to perform their task and disintegrate once the job is done.

For these reasons, scientists believe that the molecule exhibits all the attributes of an efficient “cargo” system for delivering drugs and other biomolecules into the cells. Its delivery mechanism is so good that it can even dupe the ever-agile immunity cells.

So why couldn’t some of these virtues of clathrin be exploited and developed into a drug delivery system? Many scientific groups would have loved to try it, but for one problem — synthesising clathrin in the lab is next to impossible as it has nearly 6000 amino acids, the building blocks of proteins.

Researchers led by Verma and Ehud Gazit of Tel Aviv University, however, came up with a better idea. Why not make a molecule that is structurally and functionally similar to clathrin but simpler chemically?

They did exactly this and created a similar scaffold from two rather simple chemicals — tris(2-aminoethyl)amine (tren) and tryptophan. The resultant synthetic triskelion building blocks had a structure very similar to clathrin, but the number of chemical sub units in each molecule was just six.

More importantly, when these assembly units were exposed to a chemical mixture containing methanol and water at 37 degrees — the temperature of the human body — they instantaneously started forming nano rings.

“Actually, the first few molecules self assemble and create a ring-like structure. Subsequently, other molecules join in and interlock, eventually leading to the formation of nanocages. All these processes happen simultaneously,” said Surajit Ghosh, an IIT doctoral student who works with Verma.

“The most important finding (we demonstrated) is the ability to engineer a bio-inspired nano-assembly by learning the rules of nature,” Gazit told KnowHow . “This is a key example for a situation in which the principles of biological self-assembly could be translated into an engineering approach for nanotechnology.”

The scientists explored the newly synthesised cages’ ability to carry, retain and deliver a desired molecule by making nanocages entrap rhodamine B dye, a chemical substance showing a fluorescent red colour. The dye particles remained trapped inside the tiny cages for days when the system wasn’t disturbed. Subsequently, the scientists increased the acidity of the mixture in which these nanocages are formed. The nanocages started collapsing, said Verma.

This is a remarkable feature. The inside of a cell is more acidic than the outside. Hence a drug molecule stacked inside the nanocage will remain stable all through the journey. But once it enters the cell, the acidic environment within it will slowly render the nanocage unstable, prompting it to release the drug.

“This is an interesting case of mimicking the natural triskelion structure of the clathrin protein,” states Ayyappanpillai Ajayaghosh, a scientist specialising in molecular self-assembly and nanostructures at the Regional Research Laboratory, Thiruvananthapuram. Ajayaghosh feels that the authors have followed a rational approach in designing the building block and succeeded in creating nano to micron sized cages.

Pinak Chakrabarti, a biochemist with the Bose Institute, Calcutta, says that the nanocages have remarkable structural integrity and the morphology remains unaltered over a prolonged period.

The scientists are currently evaluating the potential of their triskelion-shaped building blocks to deliver drug molecules as well as DNA constructs used in gene therapy to cells.

But Chakrabarti thinks the scientists may have a lot more work to do. “This is an interesting piece of chemistry that is bio-inspired, but now this chemistry has to be taken back to the realm of biology so that it can find application,” he says. The scientists have carried out the formation of the nanocages in methanol, whereas the system has to be able to function in water for it to work in biology, he notes.