Principles of Targeting
Dear Friends, I want to explain the principles of targeting in a brief manner. First I will tell you the entire concept in simple words and then we will take it in a technical manner. Suppose someone is suffering from some pain in the arm; we have the option of applying something like MOVE or RELAXYL which possesses an analgesic and anti-inflammatory drug on the place where the pain is there or we have the option of administering a tablet like VOVERON which contains a non steroidal anti-inflammatory drug like diclofenac. Let us visualize what happens in the two cases. In the first scenario the drug leaves the semisolid and enters the tissue directly beneath the skin. It enters all the cells which are inflamed and by direct action brings down the inflammation. So the drug goes into the cells where there is a problem and rectifies the problem. It goes into no other cells in the body. This is targeting. In the second situation, the tablet goes into the stomach; it disintegrates into small units; some drug dissolves; a fraction of it is unionized while a fraction is ionized; the unionized fraction is preferentially absorbed via the mucosa of the gastrointestinal tract into the blood stream. Now imagine the drug molecules circulating in the blood stream. They circulate in the blood which takes them to every nook and corner of the body and they try to get into the surrounding tissues and into their cells. But neither all tissues nor all cells accept them; drug molecules can enter only those cells which have receptors for them and in only those cells action results. So the drug molecules enter the cells where action is required; in our case these cells are the inflamed cells in the arm, and they reduce the inflammation. But they may also enter other similar cells elsewhere and cause some other unnecessary action which is described as a side effect. The problems in this second scenario are: The drug may cause gastrointestinal disturbance because it is present there in considerable quantity. When the drug is present in the blood it may be metabolized and excreted; it may be directly excreted; it may be caught by the body defence system called opsonisation and removed from the scene or it may be excreted by other body systems; it may go to cells or tissues where its action is not needed and cause side effects. A dose much higher than what is strictly required is administered because a good amount is being wasted (some without getting absorbed and some after getting absorbed). All these problems will be avoided if we go for targeting. So now let us suppose we want to target a drug to an inflammation which is lying deep within the body, say in the abdomen. We must remember that we do some special things to the drug molecules in order to target them to a particular site. In doing these things we take into consideration the properties of the drug moiety, the properties of the target site and the conditions necessary to be maintained when we are introducing a medicine into the blood stream directly. For many drug delivery systems such as tablets, capsules, liquid orals, parenterals or Transdermal drug delivery systems, the objective (if they are given for systemic action) is to place the drug molecules in the blood; that's all; their job ends there. But in delivery systems that are meant for targeted action, the objective is to place the drug at the required site or receptor, within the body, at the required rate, for the required duration of time. To accomplish this objective we do certain things to the drug molecules. I am giving a simple example case here. To send drug molecules to a tumor which has arisen in the abdomen we may adopt the following strategy. We take the drug material and we prepare nanoparticles, whose size is in between 100nm and 200nm and which consist of the drug material and an excipient such as, say, glyceryl mono stearate. A colloidal suspension of these nanoparticles is taken and conjugated with a hydrophilicity imparting disopsonizing agent such as poly ethylene glycol. This step will help us to keep the drug circulating in the blood and it helps the drug to escape body defense systems such as metabolism, excretion and opsonisation which is followed by phagocytosis. But still nothing has been done to send the drug to its target site. So now we take the Pegallated drug containing glyceryl monostearate nanoparticle colloidal suspension and now we conjugate, that is , by a chemical reaction process, we attach, a homing device , an antibody, or a ligand (ex: transferrin) to the nanoparticles. Now we sterilize this colloidal suspension and lyophilize this, so that we have a dry powder in a vial which is to be reconstituted prior to injection. When a doctor administers our injection of colloidal suspension of targeted pegallated nanoparticles into the vein of a patient who has a tumor in his abdomen, the following is expected to take place: The nanoparticles will keep circulating in the blood and will not extravasate (leave the blood capillaries and go into any tissue) into any place but the tumor. When the blood carrying the nanparticles reaches the tumour, because of the high permeability and retention capacity of the tumour, (Enhanced Permeation and Retention, EPR), the nanoparticles extravasate into the cells of the tumour. This is also aided by the attachment of the antibody we placed on the nanoparticles to the antigens that are expressed on the tumour (receptors). So thus the drug containing nanoparticles enter the tumor cells and accumulate there. Here, because of the high temperature of the tumour the glyceryl mono stearate will melt and release the drug. The drug will enter the receptors in the cell or on the cell membrane and bring about the death of the unwanted cell. The usual problem with cancer drugs is that they are meant to kill highly proliferating cells and they kill, in addition to cancerous cells, other highly proliferating cells such as the cells in the hair. That is why people taking cancer treatment lose their hair. But when targeted drug delivery systems are used, this problem will not be there, because the cells involved in hair growth will not be expressing the antigens which are expressed by the tumour cells. So these are the basic concepts involved in designing targeted drug delivery systems. The subject is taken broadly from Targeted Drug Delivery Systems by Vyas and Khar but I cannot give the exact pages as references, because this blog reflects my understanding after reading many chapters from it. But the basic concept is from the first chapter. I wish to tell more about the principles of targeting in my future blogs. Reference: Targeted & Controlled Drug Delivery (Drug Delivery to Brain); Chapter 1, S. P. Vyas & R. K. Khar. C. B. S. Publishers.
This blog does not contain any plagiarized material.