Using Enemy Resources
(appeared on 9th April 2014)

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The energy source of cancer cells may become their undoing, says S.Ananthanarayanan.

Except that they have started multiplying rapidly, cancer cells are really the body’s own cells. Methods to destroy cancer cells thus attack healthy cells as well, and this is the great challenge in cancer therapy. Different ways have hence been devised for getting drugs only to the cancer cells and leave the healthy ones alone. A leading strategy is of putting the drug into a container that is opened only when needed. Other methods are to control the size of particles, to make them more likely to enter and stay within the tumours, or even methods of guiding containers by magnetic effects or opening them with sound signals.

Drug delivery systems now use nano-carriers of drugs, with methods to improve targeting, so that drugs accumulate where the tumours are found and then the release of drugs within the tumour cells, triggered by different stimuli. The carriers could be liposomes, which are tiny spherical containers with a thin, fatty surface, or hollow particles made of polymers or inorganic substance. And the triggering stimuli could be external, like temperature, light, magnetic fields or sound, or physiological, like how acid the environment has become, chemical activity, presence of catalysts, like enzymes, or the level of glucose. For example, a particle, which becomes engulfed by a cell, would release its contents if it had an acid sensitive surface to react with the interior of the cell. Variations of abundance of agents that affect polymer covers of particles allow release of drugs within cells where the concentration is right. Specific enzymes that are produced inside specific tumours can also be the agents to release drugs encapsulated in the relevant outer cover.

The North Carolina and Nanjing group took a different route and looked at the level of available energy sources within cells to trigger release of drugs contained in bio-molecular packaging. While transfer of energy is mechanical in normal circumstances, like when a reaction is brought about by heat, the activity within cells is powered by energy released by reversible chemical changes. Energy from photosynthesis, for instance, is not transferred by directly to generate hydrocarbons, but is first stored as the energy of conversion of a specific molecule, called ATP (adesnosine triphosphate), which changes form from its precursor, adenosine diphosphate, ADP. This molecule then stores a unit of energy, which it can give up and activate another chemical or electric change, to enable metabolic action of the cell, by switching back to ADP.

ATP can come about by different processes and is then used by enzymes and some proteins to bring about different cellular processes. ATP gets generated usually by conversion of glucose into carbon dioxide, a process called cellular respiration, or by conversion of glucose into other forms within cells, a process called. Glycolysis, or by processes that involve by-products of breakdown of carbohydrates and fats.

ATP keeps getting converted back to ADP and again to ATP and is recycled many times. The human body, for instance, contains only 250 grams of ATP, and this intermediates all processes of the body, which turns ATP over to the equivalent of the body weight itself within a day.

ATP and drug release

To use ATP as the trigger for drug release, the researchers created drug carriers in the form of a nano-gel that consisted of DNA, protein and sugar. The DNA strand was tuned to detect ATP and also to hold the drug, Doxorubicin, within its structure. DOX is a model anticancer drug, used against many cancers, including cancer of the breast and ovaries and acute leukaemia. When the carrier attaches to ATP, this causes a change in its structure, which releases the drug. The other components of the carrier helped compress the carrier structure and to dock with portions that are found on cancer cells.

Trials, which were done with live mice, which had been induced to grow cancerous, and also human breast cancer cells, showed positive, clearly ATP-level-dependant release of the drug in the fluid found within the cell. The medium around the cells contains little ATP, while the interior of the cell has ATP, to enable metabolism. In the case of cancer cells, there is enhanced metabolism and many cancer cells contain enhanced levels of ATP. Control tests, with ATP analogues or a non-ATP responsive carrier, were negative, which validates the positive results.

The method was thus an ATP-triggered drug release system, which offers new avenues for exploration of more sophisticated drug delivery, which joins hands with the processes that go on within cancerous cells and makes use of the cell resources to select the cells and deliver the drugs once inside the cells.

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