Protein Modification and Encapsulation|
National Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100080, China
Pharmaceutical proteins are unstable when injected into the blood circulation. The half life is short, from several minutes to hours. The consequence is multiple injection and uncomfortable side effects. Chemical modification is an effective way to increase the longevity and efficacy of the proteins. The modification can be achieved by coupling a polysaccharide, a synthetic polymer, or another stable protein to the surface of the target protein. These extra molecules act as protectants or shielding agents against the attack by proteases or antibodies. They also enlarge the size of the molecules, preventing it from elimination by the kidney filtration. Other benefits may include the change of the surface charge to avoid deposition on the vascular wall and the specific release at the site of focus. There are, however, a number of disadvantages associated with chemical modifications. The first one is the difficulty in maintaining native activity of the protein. The second one is the problem of non-specific reaction. The active groups on the surface of the protein, e.g. amino group, thio group, carboxy group, may be excessive. They can react with the polymer in a random way, resulting in multiple couplings of the polymer. It is then impossible to obtain a uniform structure of the modified product, which can be a drawback for quality control and for drug assessment by the authority. Controllable modification with minimum loss of the activity is still to be achieved.
Encapsulation is another way of creating long circulating proteins. Biocompatible and biodegradable polymers have been used to enclose proteins in a form of microcapsule or even nanocapsule. The function of the polymer wall is to protect the protein against possible attacks by almost all macromolecules in the circulation fluid. The size of the capsule can be designed to meet the demands of site affinity to a specific organ where focus is present. The surface of the capsule may also be modulated to possess the ability of target delivery. A further advantage for encapsulation is the possibility of co-encapsulating other substances with the protein, such as a cofactor, a coenzyme, or another protein that helps the reaction. In this sense, microcapsule or nanocapsule can be regarded as an artificial cell with multiple biological functions. There are, however, also some disadvantages associated with encapsulation. Loss of activity is a big problem. Encapsulation process utilizes solvents and conditions not friendly for proteins. The protein inside of the capsule may have a limited stability due to the interaction with the polymeric wall. Upon introduction into the body’s circulation fluid, there may be a sudden release of the protein at the periphery of the capsule, resulting in overdose of the drug. The control of size and size distribution of the capsule is difficult. Dispersing by stirring, a method commonly used, could not produce a uniform particle size. Recently a novel emulsion process has been developed for the production of uniform particles, which has a potential in large scale production.