Proteins and peptides are highly potent therapeutic agents which can be used to treat an array of illnesses. Despite their therapeutic potential, their efficacy is often hampered by a number of notable limitations including: high molecular weight, instability, short half-life and immunogenicity. A variety of novel approaches and strategies are being investigated for their ability to overcome the current limitations of protein therapeutics. Here, for example drug formulation systems may be used, where lipid based vehicles, polymeric nanoparticles or microspheres can be used as a potential controlled drug delivery in a number of indications. Additionally, polymers can be conjugated to proteins to improve delivery aspects, a technique that has been in use since the 1950s. However, it was until breakthrough studies in the 1970semerged reporting enhanced stability and pharmacokinetics of molecules covalently attached to PEG moieties that the potential of such modifications for the purposes of drug delivery were appreciated.
PEG moieties are repeating units of ethylene glycol which when covalently bound to the activated peptide or protein of interest can alter the physiochemical properties of the molecule. Importantly, PEGylation is known to decrease renal clearance rates, resulting in prolonged residence in the body and to decrease accessibility to proteolytic enzymes through steric hinderance. There are a number of PEGylated proteins which have reached market for a range of indications including Leukemia, Hepatitis, Rheumatoid Arthritis and Crohn’s disease. Despite the progress made in PEGylation since the 1970s, there are still a number of important limitations associated with the use of PEG including loss of activity and binding affinity due to steric hindrance, the accumulation of high molecular weight products in the liver and potential immunogenicity issues.
A promising alternative to PEGylation is polysialylation. Here, polysialic acid (PSA) polymers, which are naturally occurring glycansthat can be conjugated to proteins of interest, resulting in increased stability and a reduction in clearance rates. PSA creates a hydrophilic shield around the protein of interest, reducing the protein’s susceptibility to proteolysis without affecting its biological activity. Furthermore, as PSA is naturally occurring, it avoids the lysosomal storage pathway of PEG and is easily metabolized as a natural sugar molecule by sialidades which are then degraded within the body.
In conclusion, advancements are continually being made in the field of protein therapeutics. Here, in addition to the development of new formulations containing nanoparticulate or colloidal sysytems, target proteins can be bound covalently to polymers in an effort to increase the safety, efficacy and therapeutic potential of such approaches.
Medical animation about improving the efficacy of therapeutic agents
This medical animation shows how proteins and peptides can be used as therapeutic agents for the treatment of a variety of diseases. However, their efficacy is often compromised by their rapid clearance from the body. To help overcome this issue, polymers have been conjugated to such therapeutic agents that promote stability and reduce clearance. This medical animation details the use of such a polymer, polysialic acid, and its various advantages over its competitors.
This is an image of a polysialic acid or PSA conjugated biotherapeutic, here PSA creates a hydrophilic shield around the active molecule, protecting it against proteolysis and improving the pharmaceutical efficacy properties of the therapeutic.
This is an image of proteolysis taking place, which results in the rapid clearance of therapeutic agents from the body via the kidneys. Polymers such as polysialic acid (PSA) and polyethylene glycol (PEG) are commonly conjugated to therapeutic agents to reduce clearance and improve stability.