Small is the New Big

Nanotechnology, which has taken the global healthcare industry by storm, has been showing a great potential for growth on Indian ground too, discovers Sonal Shukla

In the laboratory micro organisms are used, in order to examine the effects of nano-particles based materials for living rganisms

The strength of small is huge, or that is what one ought to say about the revolution called nanotechnology. And why not! Nanotechnology, a science which deals with atoms a few nanometres large, has the potential to make scientific strides across industries. In the IT sector, it holds the key to creating smaller, more efficient microchips that will make computers faster and smash existing silicon boundaries. It has ventured into textiles with smart materials like special surface coatings and cosmetics with efficient durable action.

However, healthcare is set to be one of the biggest beneficiaries of this nanotech revolution. In what ways is this technology capable of changing the face of healthcare? "Tools and techniques devised by nanotechnology will make medical procedures simpler, quicker, more accurate, and reduce side effects. Diseases will be diagnosed earlier, and in-treatment monitoring will ensure closed-loop control of therapeutics," predicts Dr Jayesh Bellare, Professor, Department of Chemical Engineering, and School of Biosciences and Bioengineering, IIT Mumbai.

According to him, smart drug dosage involves less frequent dosing and better control of therapeutic indices. Doctors will have a larger arsenal of devices, tools and techniques at their disposal to customise their treatment to individual patients. And above all, costs would be contained, because nanotechnology does not necessarily mean mega-costs. More importantly, aspects of nanotechnology have the potential to permeate lifestyles so as to raise the wellness index. This would happen through pure water, low-cost energy, food processing, improved agricultural practices, safer workplaces and more comfortable homes.

As per the study, 'Nanotechnology in Health Care' from The Freedonia Group, demand for nanotechnology healthcare products in the US is projected to increase nearly 50 per cent annually to $6.5 billion in 2009. By 2020, demand for nanotechnology healthcare products is projected to exceed $100 billon.

The small picture

"Nanotechnology research involves low investment and the return is enormous" - Dr Prof Amarnath Maitra Visiting Scientist Department of Pathology, Johns Hopkins Medical Institute, Baltimore

A nanotechnology application in healthcare is usually expressed as nanomedicine. "Use of nanotechnology in drug delivery, in vitro diagnostics, smart and multifunctional biomaterials, imaging and active implants together come under the umbrella of nanomedicine," says Dr Professor Amarnath Maitra, Department of Chemistry, University of Delhi and Visiting Scientist, Department of Pathology, Johns Hopkins Medical Institute, Baltimore, USA.

Nanomedicine may be defined as the monitoring, repair, construction and control of human biological systems at the molecular level, using engineered nanodevices and nanostructures. Nanotech in healthcare has invaded areas like drug delivery systems, pharmaceuticals, biocompatible materials, micro-engineered devices, improved cardiac catheters and stents. Some examples include nanotechnology- based synthetic bone for maxillofacial applications, for treating fractures, and as a scaffold for tissue engineering and differentiation of stem cells, nanoparticles for pulmonary and ocular delivery, and microengineered transcatheteral devices for minimally invasive cardiac surgery.

According to Dr Bellare, however, the potential impact is large, inclusive of artificial organs, tissue engineering, diagnostics of various sorts (at home, bed-side, ambulatory) battlefield, and outer space. "The impact will be felt on virtually every facet of healthcare, from pre-birth to post death," says Bellare.

"The impact will be felt on virtually every facet of healthcare, from pre-birth to post death" - Dr Jayesh Bellare Professor Department of Chemical Engineering, and School of Biosciences and Bioengineering IIT, Mumbai

"Drug delivery targeted at specific sites in the body and molecular imaging are being intensively investigated" - Dr Sanjeeb Sahoo Nanomedicine Laboratory Institute of Life Sciences, Bhubaneswar

Nano drug delivery

Nanotechnology analysts predict that nanotechnology enabled drug delivery systems will generate over $1.7 billion (US) in 2009 and over $4.8 billion in 2012. The global drug delivery products and services market is projected to surpass US$67 billion in 2009.

Nanotechnology can be incorporated in a wide range of oral dosage presentations including: tablets (including immediate-release film coated, modified release, orally disintegrating tablets), capsules (including immediate-release, modified-release), liquid dispersions and powders. "Apart from offering a solution to solubility problems, nanobiotechnology provides intracellular delivery possibilities," says Shukla. Skin penetration is improved in transdermal drug delivery. A particularly effective application is non-viral gene therapy vectors. Nanotechnology has the potential to provide controlled release devices with autonomous operation guided by needs. "Applications of nanotechnologies in medicine are especially promising, and areas such as disease diagnosis, drug delivery targeted at specific sites in the body and molecular imaging are being intensively investigated and some products are undergoing clinical trials," says Dr Sanjeeb Sahoo, Nanomedicine Laboratory, Institute of Life Sciences, Bhubaneswar. In therapeutic process, nanotechnology has two specific roles: (i) entry of drug into the cell by endocytosis only using nanoparticles as carriers and (ii) targeted delivery of drug to the desired tissue or cell so as to minimise side effects.

Targeted impact

Nanotechnology can drastically reduce drug dosages and side effects. When drug molecules are administered into the body particularly in the systemic circulation, they extravagate to all parts of the body by diffusion and move freely in and out of the cell. These small drug molecules have unrestricted access to diseased as well as normal tissues in the body. When a certain amount of drug is administered, only a very small and insignificant amount goes to the diseased tissues while major part goes to non-diseased sites in the body causing toxic side effects. "The best example is the use of an anticancer drug in chemotherapy which has access to all parts of the body killing not only cancer cells but also normal cells," explains Dr Maitra.

When the same drug molecule is wrapped in nanoparticles, it cannot diffuse inside the cells but permeates through endocytosis. This is one-way traffic. The drug-loaded nanoparticles are usually carried by the endosomes to the lysosomes and are degraded by the enzymatic process—so the free drug comes out and manifests its therapeutic action. Moreover, the nanoparticles are tailor-made chemical entities and so surface modification of these nanoparticles with suitable molecules is possible. These molecules help recognition of these particles by the cell surface. As a result, one can have targeted delivery of drug to the desired sites in the body (say diseased tissues) and thereby reduce the side reaction.

If we assume that one drug molecule can kill one cell and 1000 is the molecular weight of drug molecule, then 1013 drug molecules can kill all the cells in the body which comes out to be about 100ng of drug. Dr Maitra cites an example of treatment of throat infection by antibiotics. The patient takes a couple of hundred milligrams of antibiotics. "If we consider that one antibiotic molecule can kill one bacterium in the body, then we need only few nanograms or even less of the drug. If the antibiotic is loaded in engineered nanoparticles which can be orally administered and can be targeted to the throat bacteria, one can have the same or better therapeutic effect with a few nanograms of drug with significantly reduced side effects," he explains. This is due to the combined effect of endocytosis and targeting. This is how nanotechnology can change the face of healthcare sector, eliminating the wastage of drug by targeted delivery and minimisation of side effect. In the near future, the most important clinical applications of nanotechnology are likely to be in pharmaceutical development.

Says Dr Sahoo, "There are already an astonishing number of emerging applications. These applications either take advantage of the unique properties of nanoparticles as drugs or components of drugs per se or are designed for new approaches to controlled release, drug targeting and salvage of drug with low bioavailability." For example, nanoscale polymer capsules can be designed to break down and release drugs at controlled rates and to allow differential release in certain environments, such as an acid milieu, to promote uptake in tumours versus normal tissues. "Substantial research is now devised for creating novel polymers and exploring specific drug-polymer combinations," he adds.

Nanotechnology is opening new therapeutic opportunities for many agents that cannot be used effectively as conventional oral formulations because of their poor bioavailability. "In some cases, reformulation of a drug with smaller particle size may improve oral bioavailability," says Dr Sahoo.

Nano molecular diagnostics: Some of the earliest applications of nanotechnology in pharmaceuticals are in molecular diagnostics. Because of the small dimensions, most of the applications of nanobiotechnology in molecular diagnostics fall under the broad category of biochips/microarrays. Biochips constructed with microelectromechanical systems are on a micron scale and related to micromanipulation, whereas nanotechnology-based chips are on a nanoscale and related to nanomanipulation. "Even though microarray/biochip methods making use of the detection of specific biomolecular interactions are now an indispensable tool for molecular diagnostics, there are some limitations," Dr Sahoo concedes. DNA microarrays and enzyme-linked immunosorbent assays rely on the labelling of samples with a fluorescent or radioactive tag, a highly sensitive procedure that is time-consuming and expensive.

Nanotechnology is being applied to overcome some of the limitations of biochip technology. "Nanotechnology on a chip is one more dimension of microfluidic/lab-on-a-chip technology. Biological tests measuring the presence or activity of selected substances become quicker, more sensitive and more flexible when certain nanoscale particles are put to work as tags or labels," explains Dr Sahoo. According to experts, nanotechnology on a chip is a new paradigm for total chemical analysis systems. The ability to make chemical and biological information much cheaper and easier to obtain is expected to fundamentally change healthcare, food safety and law enforcement. "Numerous nanodevices and nanosystems for sequencing single molecules of DNA are feasible. Various nanodiagnostics that have been reviewed will improve the sensitivity and extend the present limits of molecular diagnostics," opines Shivani Shukla, Programme Manager Healthcare Practice, Frost & Sullivan.

Nano in imaging: According to experts, nanotechnology has displayed the potential to transform the field of medicine, because it offers novel opportunities for sensing clinically relevant markers, molecular disease imaging, and tools for therapeutic interventions. "Nanotechnology already affords the possibility of intracellular imaging through attachment of Quantum Dots (QDs) or synthetic chromophores to selected molecules. Proteins, for example, or by the incorporation of naturally occurring fluorescent proteins that, with optical techniques such as confocal microscopy and correlation imaging, allow intracellular biochemical processes to be investigated directly," explains Dr Sahoo. QDs are semiconductor nanocrystals with unique optical and electrical properties. Among others, one of their most valuable properties is their fluorescence spectrum, which renders them optimal fluorophores for biomedical imaging.

Nano gene therapy: Gene therapy is a recently introduced method for treatment or prevention of genetic disorders by correcting defective genes responsible for disease development based on the delivery of repaired genes or the replacement of the incorrect ones. "The most common approach for correcting faulty genes is by insertion of a normal gene into a non-specific location within the genome to replace a non-functional gene," explains Dr Sahoo.

Nano cardiac therapy: Today, nanotechnology offers a broad platform in the field of cardiovascular science at the cellular level. "Nanotechnology-based tools can be effectively used to treat cardiovascular diseases. These tools can be used in the areas of diagnosis, imaging and tissue engineering," says Dr Sahoo. Miniaturised nanoscale sensors like QDs, nanocrystals, and nanobarcodes can sense and monitor biological signals such as the release of proteins or antibodies in response to cardiac or inflammatory events.

Nanotechnology can also help in revealing the mechanisms involved in various cardiac diseases.

Nanotechnology can also be an effective answer to curb restenosis— the obstruction of an artery after interventional procedures such as balloon angioplasty and a major problem with 30-50 percent of patients developing reocclusion, with 20 per cent requiring additional intervention. "Although different therapeutic strategies have been investigated for the inhibition of restenosis, the main drug therapy approach is targeted toward inhibiting the proliferation and migration of smooth muscle cells. Systematic administration of therapeutic agents has been ineffective in preventing restenosis," states Dr Sahoo. According to him, researchers have a great hope that nanotechnology-based localised drug therapy using sustained-release drug delivery systems could be more effective, because it can provide higher and prolonged drug levels in the target tissues without causing systemic toxicity.

Nano dentistry: Nanodentistry will bring the maintenance of near-perfect oral health through the use of nanomaterials, biotechnology and nanorobotics. "In the years to come, it will be possible through nanodentistry to induce local anaesthesia with the help of active analgesic dental nanorobotic particles. Apart from this, nanodental techniques for major tooth repair may also evolve," Dr Sahoo forecasts.

Moreover, nanodentistry could also play a vital role in natural tooth maintenance wherein appearance and durability of teeth may be improved by replacing upper enamel layers with covalently bonded artificial materials such as sapphire or diamond, which have 20 to 100 times the hardness and strength of natural enamel.

Nano orthopaedics: Musculoskeletal disorders have become a major concern today, given an aging population and an increased occurrence of sports-related injuries. Current treatment modalities include orthopaedic implants used for internal fixing of fractured bones. These, however, have been bogged down by the problem of implant failures. Says Dr Sahoo, "Nanotechnology can provide an alternative platform with higher mechanical strength, enhanced bioavailability, and resorbability to improve the quality of life of patients who suffer from debilitating bone fractures."

Applications of Nanotechnology

Courtesy: Frost & Sullivan

Indian nano

The Indian scenario for nanotechnology research, while still nascent, has been showing an increased level of interest. Indian nanotechnology work impinging on healthcare is in the field of nanomaterials and nanocomposites, nanoparticles, imaging technology for high-resolution microscopy. Government funding agencies particularly the Department of Science and Technology, and the Department of Biotechnology are funding research as well as private-public partnership projects in this area. "Some doctors interested in research and working in hospitals are actively collaborating with the IITs for innovation. Some forward-thinking industries are also working towards this," says Dr Bellare. Some active institutions in nanotechnology research arena include AIIMS, Tata Memorial Centre, Nanavati Hospital, Glenmark and Nicholas Piramal. According to some, research in nanotechnology on Indian soil still has miles to go. Says Utkarsh Palnitkar, Partner, Ernst &Young, "Oncology is the only therapeutic area wherein nanotech is being applied in India, although the potential is immense since it can be applied for any targeted therapy."

"Nanotechnology in healthcare should be considered as one of the important areas of research in India because it involves low investment and the return is enormous so far as the public benefit is concerned," opines Dr Maitra.

Future in devices

According to Dr Maitra, the Indian pharma industry is interested in quick money and therefore they are more involved in generic drugs and exporting them. In 2007 alone, $18 million of generic drugs have been exported. On the other hand, academia are only interested in mediocre basic research and publications.

Although the share of nanotechnology in the drug delivery market is growing by leaps and bounds, it is shadowed by some concerns. "It is widely observed that while big pharma companies are 'flat footed' in their initiative about nanotechnology, medical device companies are more aggressive in pursuing nano technological strategies," says Shukla.

sonal.shukla@expressindia.com