Passive targeting Passive targeting or physical targeting involves the preparation of a drug carrier complex that can avoid the elimination due to body defence mechanisms like metabolism, excretion and opsonisation followed by phagocytosis. The complex will keep circulating in the blood stream and allow itself to be taken to the target receptor by some body property like pH or warmth or molecular size or shape. To prepare a drug molecule into a device that can keep circulating in blood and connect only to the required receptor, many of its properties are critical or important. Such properties are its molecular weight, charge on the surface, hydrophobic or hydrophilic nature of its surface and its size. Whether the device can destabilize the membranes of the body and whether it is sensitive to triggering signals like pH and temperature is also important. So the properties of the drug molecule and the properties of the drug, carrier complex are both important. Molecular Weight: Only delivery systems that have a total (drug+carrier) molecular weight of more than 30 Kda can escape quick renal clearance and keep circulating in blood. The microtubular cells of the kidney quickly filter and eliminate molecules which are less than 30 Kda and which are hydrophilic. This molecular weight will make the complex big enough so that it will not be filtered. Molecular Size: So how big should the size be? The size of the total complex should not be more than 200 nm. This is because the delivery system must be able to penetrate the openings or fenestrae of the endothelial cells of the capillaries. For most normal capillaries the endothelial cells are attached to one another tightly (no chance for molecules to filter out or penetrate), on a continuous subendothelial membrane. Only small systems of sizes less than 10 nm can filter out or penetrate out of these junctions into extravascular tissues. But tumour tissues, which we are targeting have blood capillaries with not so tight junctions and their fenestrae are big, they are filters with big holes and they allow systems upto 200 nm. But only systems upto 200 nm can penetrate; bigger than that size cannot penetrate. Anyhow it is also difficult and not wise to give IV injections having systems of sizes more than 200 nm as they may cause blocking of the blood capillaries. Under normal circumstances the liver, the spleen and the bone marrow have capillaries with large pores or openings. Solid tumors are also like this. Nature of surface: The nature of the surface of the delivery system should be hydrophilic to avoid removal by the monophasic phagocytic system. This system, known as the MPS system is on the watch, looking out for hydrophobic systems. If a hydrophobic system enters the blood circulation, the MPS views it as a XENOBIOTIC and tries to attach to it. What are called as opsonins (Body proteins) attach to it and they are like markers. Once they are marked by the opsonins, the macrophages in the blood imbibe them and remove them into the reticuloendothelial system composing of the liver, spleen and bone marrow. * So if we want to escape this opsonisation and phagocytosis system we must attach to our delivery system hydrophilicity imparting agents such as poly ethylene glycols. This procedure is called steric stabilization. Liposomes which are coated with PEG are called stealth liposomes as they are cheating the body into believing that it is not a foreign body and are managing to circulate in the blood. Surface Charge: Whether the surface of the drug delivery system has a positive or negative charge or is neutral in charge indicates for how long it can circulate in the blood. If the systems have a negative charge they are removed from the circulation quickly by the Kupffer cells in the liver. If their charges are positive they are recognized as foreign bodies by the opsonins and are removed from circulation. Only neutral systems have a long circulation time in the blood. So we have to modify or design the molecular weight of the system, size of the system, surface hydrophobicity and surface charge of the system to keep it circulating in the blood and for it to go to the expected target. In addition we can attach a protein that can destabilize the natural biomembranes and penetrate them. Let us now see the next component of our design; triggered release. That is, we make the delivery system in such a way that it responds to some physical property such as pH, temperature or charge in the body in the target area and releases the drug only in that area and nowhere else. Another modification of this principle is the triggering mechanism is supplied from outside the body. Let me explain all this more clearly. For example we can prepare a liposome and make its coat such that during circulation in blood it is stable but when it goes into the capillaries in the tumor where the temperature is a little bit higher the coat must melt and release the drug which must accumulate it the tumor and cause its action. These are thermosensitive liposomes. Or we can attach the drug to the carrier by means of a molecule called linker which is labile to a particular enzyme which is found only in the target tumor. An example for external stimuli is this: We prepare a delivery system and attach a something to it which responds to magnetism. We give the IV injection. Now our magnetized delivery system is circulating in the blood. Suppose the problem is in the abdomen and we want the drug to localize in the abdomen; we make the patient lie down and apply magnetism from outside on the abdomen. Then beneath the surface of the abdomen the magnetic targeted delivery systems will accumulate. Other examples of passive or physical targeting: 1. Suppose there is a tumor in the liver. We send drug carrier complex that is having the proper size, molecular weight and charge but is hydrophobic in nature. Now opsonins will attach to it, it will be phagocytosized and will be left in the liver; that is what we want. 2. Suppose there is a target in the blood and not in the liver. We want the drug carrier complex to go on circulating in the blood and slowly release the drug. Now this is the strategy. First we give a good volume of placebo injection like dextran IV injection. The opsonins and the phagocytes will all be consumed by these dextran molecules and the reticuloendothelial system will be saturated. Now we give the real drug- carrier complex injection which will serve its purpose by staying in the blood for a long time. In a nutshell! 1. Passive or physical targeting involves preparing the delivery system of a definite molecular weight(>30Kda), molecular size(100-200nm), having hydrophylicity and neutral charge. 2. The physiological conditions in the tumor are considered. The physical properties of the target are studied. 3. We can do targeting by adjusting the delivery system to be sensitive to pH or temperature or charge or an enzyme. 4. The triggering mechanism may be supplied from outside the body also. 5. Targeting to the reticuloendothelial system or the circulatory system may be done by passive targeting. Reference: Design of Controlled Release Drug Delivery Systems, Xiaoling Li, Ph.D, Bhaskara R. Jasti, Ph.D, McGraw-Hill publishers, Chapter 11, Physical Targeting Approaches to Drug targeting, pages 339-375. This blog does not contain any plagiarised material.