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The goal of this proposal is to develop novel drug delivery systems that can be used for the
controlled release of cancer drugs at the exact site of tumor by modifying the DNA- based hand.
The recent advancements in the field of nanotechnology have paved the way for the
development of a DNA± based hand which can be controlled to take up and release Į-thrombin
(blood clotting protein) in a highly controlled manner. The DNA± hand is constructed using an
aptamer ( short stretch of DNA or RNA which can selectively bind to a protein molecule ).The
opening of the DNA- hand is facilitated by the addition of short DNA strands ( opening strands )
which bind to a part of the DNA- hand and confer a double stranded conformation to the DNA±
hand. This process can be reversed by the addition of short DNA strands which remove the
opening strand. By exploiting this property of the DNA hand, it can be directed to carry cancer
drugs and release them in a highly controlled manner. This can be thought of as an ³Intelligent
Drug Delivery System´ The controlled release of the cancer drugs would reduce the risk of the
normal healthy tissues being affected. This would reduce the possible side effects, which are
otherwise seen in case of chemotherapy and radiotherapy procedures. The DNA±based hand
can be modified to carry drugs which would combat the cancer at different stages.

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Cancer, due to its incidence among the populations in both developed and developing countries
has been a subject a immense interest for scientists trying to develop new drug delivery
systems for treating fatal diseases. If we look at the increasing number of deaths caused due to
a multitude of cancers, we can understand the magnitude of the problem. But the foray of
nanotechnology into the field of medicine has made it easy for scientists to develop intelligent
drug delivery mechanisms and novel drugs which can be used for treating life threatening
diseases without the fear of harmful side effects. Cancer is basically the condition in which the
cells of the body lose their capacity to multiply in a controlled manner and as a result divide at
alarmingly high rates. This leads to the growth of tumors in the body, which are found to
interfere with the normal functioning of the cells. There is a lot of diversity in the treatment
procedures employed for the treatment of cancers. Chemotherapy and radiotherapy are
considered to be the initial treatment procedures which are used to cure cancers in the early
stages. In advanced conditions of cancer, surgical removal of the tumors is the last resort. All
these procedures have their own drawbacks. If we consider the chemotherapy procedure, which
basically is the administration of chemicals which kill the tumors, there is a high risk of healthy
cells surrounding the tumors being destroyed. Similarly, radiotherapy is the treatment procedure
in which radioisotopes are used to treat cancers. This was also found to significantly destroy the
healthy cells surrounding the cancer cells. Cardiomyopathy and neuropathy are the fatal side
effects caused due to chemo and radiotherapies. Conventional drugs pose another problem of
 diffusing all over the body and showing effects in undesired sites. This can be attributed to the
low molecular weight of the conventional drugs.

Cancer cells show a wide variety of properties like angiogenesis,

metastasis etc, which aid in the transport of the cancer cells from the site of initial development
to other sites all over the body. To circumvent this problem and the others outlined above, drug
delivery systems which target the cancer cells at various stages of their development and which
act at the site of tumor with pin point accuracy need to be developed. To achieve this, the DNA-
based hand is constructed in such a way that it can distinguish between the normal cells and
the cancer cells and which can release the drug in a controlled manner. The excess drug
molecules at the site of the tumor are also taken up by the modified DNA- hand so that there
would not be any side effects due to the accumulation of drug at the tumor site.

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Constructing a DNA- based hand which can carry the tumor suppressor protein E- Cadherin

Cadherins are a class of cell adhesion receptors. Cancer cells lack this class of receptors, as a
result of which the cancer cells can move freely in the blood circulation and move to various
other parts of the body away from the site of tumor. The DNA- hand is constructed using an
aptamer which can bind the cadherin molecule. This can be achieved by the systematic
evolution of ligands by exponential enrichment ( SELEX ) process, through which the isolation of
oligonucleotide sequences that recognize virtually any class of target molecules with very high
specificity and affinity is possible. The DNA- hand also carries a protein which can specifically
recognize any of the cell surface receptors specific to the cancer cells like retinoid receptors or
estrogen receptors or epidermal growth factor receptors and EMMPRIN (Extra cellular Matrix
Metalloproteinase Inducer) receptor. The DNA- hand can be directed to release and take up the
drug molecule after reaching the target site by the addition of short stretches of DNA which
open and close the hand in a controlled manner.

The DNA± hand for carrying the drugs which target metastasis and angiogenesis are
constructed in the similar manner as mentioned above except for that the drug molecule
attached to the aptamer is changed.

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1. Dittmer, W. U. , Reuter, A and Simmel, F. C. (2004) A DNA-based machine that can cyclically
bind and release thrombin. „

s , 3550-3553
2. Alberti, P and Mergny, J. L. (2003) DNA duplex-quadruplex exchange as the basis for a
nanomolecular machine. Y
 
„„Ä , 1569-1573
3. Bock, L. C., Griffin, L. C., Latham, J. A., Vermaas, E. H., and Toole, J. J. (1992) Selection of
single-stranded-DNA molecules that bind and inhibit human thrombin. 
 

, 564-566
4. Liu, D. S and Balasubramanian, S. (2003) A proton-fuelled DNA nanomachine. „


s, 5734-5736