The guiding principle behind drug delivery has always been to get the ability to scratch right where it itches. One of the most critical rate limiting steps in drug discovery is to ensure the efficient delivery of the drug. In principle, any inhibitor of a cell or molecule can be used as a medicine, if it can be selectively delivered to its intended place of action. Most often, this is where the problem comes up, resulting in problems in systemic toxicity and unacceptable ADME values. Drug delivery has thus become an important field of research in the pharma industry in recent times, starting from the mid 1950s. It began with the introduction of the first microencapsulated drug particles, which soon paved the way for the use of polymers in drug delivery in the mid 1960s.

This was the time when the pharma industry started a systematic approach to product development that also took into account the problem of drug delivery quite early on. Since then, there have been quantum improvements in the technology of delivering drugs orally, transdermally and transepithelially. Various forms of controlled release methods now allow drugs to be delivered in a more physiological manner leading to greater bioavailability and efficacy. With the advent of biopharmaceuticals like peptides and proteins, liposome mediated delivery of these drugs has been introduced to allow the transport of the drug to specific target tissues and organs in the human body. After about 20 years of research efforts, polyethylene (PEG) coated liposomal drugs are now routinely used to treat cancers and systemic fungal infections. Till now, drug delivery research has typically aspired to improve the pharmacokinetic profile of drugs to make them more cost-effective, convenient and safe for the patient. Research in this field has kept pace with developments in our understanding of etiology of diseases. However, major challenges still remain.

For example, drug delivery across the blood brain barrier still poses significant problems. To treat neurodegenerative and psychiatric diseases, effective delivery of the drug to the brain and elsewhere in the CNS needs to be realized. Moreover, our understanding of newer diseases and disease mechanisms has led to the identification of many intracellular drug targets, which has set newer and more ambitious goals for drug delivery research. Two promising new drug delivery technologies hold the cue to revolutionizing the future of medicine. Both of these technologies are based on a fusion of ideas derived from nanoscience and molecular biology.

NANOPARTICLE MEDIATED DRUG DELIVERY

Nanoparticles are solid, colloidal particles that range in size from 10 to 1000 nm. Nanoparticle mediated delivery of drug is useful particularly in disorders of the brain, where the delivered drug has to cross the blood brain barrier. This is achieved in this case due to the extremely small size of the drug particles. The dissolution and absorption of a drug depends on its surface area, other parameters remaining constant. Therefore, as the particle size decreases, the total surface area that becomes available increases exponentially. These days, oral and ophthalmic nanoparticle mediated delivery systems are already in vogue, and nanoparticles are being increasingly used as an alternative to liposomes as drug carriers. For this purpose, the drug is dissolved, entrapped or absorbed in the macromolecular material to enhance it's bioavailability. One of the advantages that this technology offers is the improved delivery of water insoluble drugs. This is done by transforming the drug into nanometer sized particles that can be incorporated into common dosage forms, including tablets, capsules, inhalation devices and injectables. A nanoparticle based long lasting injectable for Schizophrenia by Johnson & Johnson is already in advanced clinical trials.

In spite of the huge advantages offered by nanoparticle mediated drug delivery, the technology suffers from some intrinsic limitations. For example, not all diseases are curable by chemical or biological compounds. Many inherited and genetic diseases for example, can only be treated by replacing the defective copy of the gene by a normal copy. In some cases, a faulty transcript needs to be blocked from getting translated into a functional protein. In cases like this, nanoparticles are of little or no use, and bolder ideas need to be experimented with.

MOLECULAR MOTOR MEDIATED DRUG DELIVERY

With the understanding of genetic diseases, and a deeper understanding of cell biology, the idea of tinkering at the very level of genes to ameliorate their malfunction came into vogue. Thus the concept of gene therapy was floated. The idea was to package genetic materialinside synthetically doctored viruses that could deliver it right inside the cell. However, in spite of widespread hype and much effort, so far the idea has met with limited success. The main hindrances seem to be two in number. Firstly, there have been problems associated with the designing and delivery process itself. But more importantly, almost all of these efforts led to the eliciting of unfavorable systemic immune reactions. But the idea of using a Trojan horse to escape the body's defense is indeed an intelligent one. Recently, the same idea has been readapted to deliver genetic material inside cells using intracellular molecules that serve as motors. Molecular motor mediated gene therapy thus holds the potential to represent the next quantum leap in drug delivery technology Molecular motors make up the intracellular transport system in all cells of our body. Think of them as subway trains that ply in the city traffic. Only in this case the railroad is made up of protein filaments called actin and microtubules. Research in cell and molecular biology in the last decade has led to a great deal of knowledge about these molecules and the technology to tinker with them to suit our purpose now exists. Molecular motors are, in reality, nanomachines that are required in the cell to carry molecular cargo useful in regular processes like cell division, motility, vesicle transport etc. The motor proteins have a distinct head domain which attaches to the rails and a tail domain with which it binds cargoes. There are three types of these motor proteins inside the cells; kinesins, dyenins and myosins. Out of these, kinesins and dyenins are involved in long distance intracellular transport of cargoes along microtubule tracks which run from the cell periphery(+ end) to the nucleus in the centre of the cell(- end).While most kinesins move towards the nucleus towards the cell periphery, all dyenins and few kinesins carry their cargo in the opposite direction towards the nucleus.

It has recently become possible in experimental models to bioengineer motor proteins to modify their speed, directionality, cargo specificity etc. Though this is an ongoing field of research, scientists are optimistic about being able to design motor proteins that would be able to perform novel functions like improving non-viral gene therapy. There is widespread consensus that engineered molecular motors could be used as vectors to deliver DNA or drugs right inside the cell. This can be achieved either by inducing the formation of new microtubule tracts in the cell and adding motors that can carry the necessary cargo along these tracts to deliver them in the cells Alternatively, the existing microtubule network of the cell can be used in conjunction with modified motors to facilitate the delivery of its drug cargo. These elegant principles have already been validated in laboratory scale experiments, and therefore offer considerable hope of being realized in the clinic as well. Current research in various laboratories is going on to enhance the feasibility of this approach.

However elegant though it may seem, the transition to a feasible technology is still fraught with many problems in the case of molecular motors. Firstly, the dynamics and regulation of cargo binding to the motors need to be elucidated in much greater details. Only then would it become possible to bind any drug at will to a designated motor protein to be carried inside the cell. Equally serious is the problem of inducing the binding and aggregation of cargo and motors inside the cell for the process to start. Only after these hurdles have been negotiated can this technology be tested in clinical trials and eventually adapted in the industry. Depending on how things go, this could take quite some time. However, there is no doubting the fact that the idea is an extremely powerful one, and when realized, will revolutionize the field of medicine. Though it might seem futuristic now, molecular motors could one day be the delivery vehicles of choice for treating neuropsychiatric disorders, genetic abnormalities, neurodegenerative diseases and malignant tumors. It is then that the widely spoken concept of personalized medicine will become a reality.


(The author is regulatory CMC manager, Global Reg. CMC, Novartis AG, Switzerland)