Drug Delivery with PEGylation

In 2006 the modern biopharmaceuticals market was worth over $40.3 billion in the US and over $45 billion worldwide (IMS Health, Inc). It is projected to grow to an annual value of some $100 billion within the next five years. The big advantage of proteins, antibodies, siRNA and other natural products in their usage as drugs is their high specifity in combination with their low side effects. They normally interact only with the dedicated target, and thus do not have an impact at any other place in the body. A current focus is the study of modern drug carrier systems, where polyethylene glycol linkers are connecting a recognition part with a drug-active part (1,2).

Such conjugations can reach the size of a nanoparticle. The recognition part can be a peptide or hormone, which binds specifically to the surface of a certain cell. After internalisation of the whole nanoparticle, the active part (DNA or siRNA, for example) is released. Inhibition or activation of certain enzymes or the nucleus follows, consequently repairing the sick cell, to shut it down by initiating apoptosis or other mechanisms. In conjugation with hydrophobic compounds forming amphiphilc and biodegradable block-copolymers like PEG-PLA (polylactic acid) and PEG-PLGA (co-polylactic acid-glycolic acid), sophisticated micelles are formed where drug molecules can be masked and protected against attacks of the immune system (3).

Modern biopharmaceuticals are ideal drugs; however, a significant drawback is their low stability under physiological conditions. Due to the fact that they are similar to biological components, they are also easily attacked by the body’s immune system (that is, by antibodies and proteolytic degradation enzymes). Many efforts have been made, using highly sophisticated formulation techniques, special application methods (depots), and chemical modification, to improve their pharmacokinetic properties. One recent approach, which shows much better results than other methods tried in the past, is PEGylation – that is, attaching polyethylene glycol chains (PEG) to the active component. The simplest possible use of PEGylation is attaching a monofunctional PEG chain to a protein, antibody or small drug molecule. Through using bifunctional PEGs, a link between two compounds can be formed in order to build dimers or more complex conjugates. Many highly sophisticated compositions are under development and have already been published.

WHY PEGYLATION IMPROVES DRUG DELIVERY AND PHARMACOKINETIC

Small drug molecules or proteins suffer a rapid clearance. The concentration of the drug compound drops rapidly as it is removed from the body. Application has to be repeated in order to keep the concentration over a certain threshold. Otherwise immunogenic reactions start and resistant derivatives are formed. PEGylated drugs show suppressed renal clearance and reduced immunogenic reaction, and the concentration is slowly reduced over the treatment period. In the ideal situation, only a single application is required over the time of treatment (4). This is due to two mechanisms.