Albumin
Albumin functions and features
Introduction to albumin
Preclinical and clinical studies highlight the potential of albumin for a variety of applications, including drug delivery1
Albumin is a highly versatile protein thanks to both its oncotic and non-oncotic properties. It is the most abundant protein in extracellular fluid and in the blood, representing around half of all serum proteins2,3. Albumin weighs approximately 67 kDa, is water-soluble, globular and negatively charged at neutral pH3. Albumin is one of the most important proteins1, with multiple functions including ligand-binding, transportation and compound distribution and metabolism4.
In this video, Alastair O’Brien, Professor of Experimental Hepatology at University College London, describes the various roles of albumin in the body. Professor O’Brien describes the oncotic and non-oncotic properties of albumin, including its role in drug transportation, its binding properties and anti-inflammatory effects.
Albumin is a heart-shaped molecule consisting of three domains of similar size, each divided into two subdomains. Within subdomains IIA and IIIA are two important binding sites named Sudlow I and II, which bind hydrophobic compounds, including hydrophobic drugs1. Figure 1 illustrates the molecular structure of human albumin.
Figure 1. Molecular structure of human serum albumin5. Molecular structure of human serum albumin is licensed under CC BY-NC-ND 4.0. The crystal structure (pdb code 1e7i) of human serum albumin shows the six subdomains (IA, IB, IIA, IIB, IIIA and IIIB), the N and C termini, Sudlow’s sites I and II, and the seven long-chain fatty acid (LCFA) binding sites (FA1 to FA7). The heavy atoms of the side chain of residue Cys34 are shown as purple spheres. LCFA binding sites also bind prostaglandins. Cys34 binds reactive oxygen species and reactive nitrogen species, including nitric oxide.
Synthesis and metabolism of albumin
Albumin is synthesised by hepatocytes and excreted into the bloodstream3. Up to 60% of albumin is stored in the interstitial space rather than in circulating blood, lasting just 16–18 hours in circulation, compared with its biological half-life of 19 days1. The normal concentration of human albumin is 35–50 g/L4 and the effective concentration depends on its movement between interstitial and intravascular spaces, and the balance between albumin production and degradation1.
Albumin is constantly synthesised and recycled by hepatocytes, recycling accounting for its longer biological half-life. Albumin is regulated by the neonatal crystallisable fragment receptor (FcRN), which binds albumin on the surface of epithelial cells and hepatocytes3. FcRn redirects albumin away from the extracellular space and bile, and into the vascular space3. The expression of FcRn by epithelial cells and hepatocytes is the primary driver of circulating albumin levels and recycling, and its absence contributes to hypoalbuminaemia3. Figure 2 illustrates albumin metabolism.
Figure 2. The metabolism of albumin by Bernardi et al3. Albumin recycling by endothelial cells is licensed under CC BY-NC 4.0 / image redrawn and colours altered. FcRN, neonatal crystallisable fragment receptor.
Given the reversible transcapillary movement of albumin, plasma concentrations can be maintained at a constant level1. The body’s requirements regulate its production, with thyroxine, cortisol, insulin and conditions such as hypoalbuminaemia being particular stimulants for production. In contrast, high levels of osmotic pressure on hepatocytes reduce its production1. Nutrient supply must be at adequate levels to trigger the production of albumin, and indeed the liver’s ability to produce protein is hindered when nutrient absorption is poor1. Albumin degradation mainly occurs in the liver and kidney but can occur in any tissue1.
As it is produced by the liver, functional liver loss can lead to decreased albumin levels1. Its levels can decrease when production by the liver is affected, in which case there may be an increase in protein breakdown and greater protein loss via the kidneys, expanding plasma volume and diluting the blood1. Albumin concentration can also be affected by kidney disease1.
Functions and features of albumin
Albumin has several roles in the body, its two key roles being to maintain osmotic pressure in the blood, and to be the primary carrier of hydrophobic materials such as hormones and fatty acids1.
Albumin transports vitamins, hormones, drugs and divalent cations such as zinc and calcium, and it nourishes tissues1. It is involved in wound healing and coagulation, has antioxidant properties, enhances antithrombin III activity and, in inflammatory conditions, it acts as a free radical scavenger1. Albumin is the key factor determining plasma oncotic pressure and is pivotal in controlling fluid distribution between compartments6.
Albumin is the primary antioxidant in the human body that7:
- Regulates immunological and inflammatory pathways
- Helps regulate endothelial integrity
- Plays an essential role in detoxification and transport
- Counteracts reactive nitrogen and oxygen species
The many functions of human serum albumin are summarised in Figure 3.
Figure 3. The functions of albumin (Adapted8).
The roles of albumin in the body9:
- Anti-inflammatory activity
- Binding and transport of materials (naturally occurring, therapeutic and toxic)
- β-amyloid peptide
- Bilirubin
- Drugs
- Circulating ions
- LCFAs
- L-tryptophan
- Steroids
- Contributes to plasma pH
- Determines plasma oncotic pressure
- Immunomodulation
- Regulates haemostasis
- Regulates intercompartmental tissue fluid distribution
- Scavenges oxidative and nitrosative reactive species
- Stabilises endothelium, capillary permeability and vascular integrity
Clinical applications of albumin
While albumin can be extracted from various sources including egg white and human, rat or bovine serum, bovine serum albumin and human albumin are the most common forms used for drug delivery1. Human albumin solution (HAS) is also primarily used for fluid resuscitation and to treat critically ill patients with hypoproteinaemia10.
HAS is nonimmunogenic and the body does not recognise it as foreign material unless it is altered or damaged1. It is a highly versatile carrier protein, possessing many functions, and is used in a wide range of clinical applications including volume replacement, drug delivery, and as a prognostic biomarker4,9. Researchers postulate that albumin could also be used for other applications such as the production of nanovaccines1. Given its ability to actively target disease sites without the need for addition of specific ligands, it could potentially promote half-life extension and targeted drug delivery1.
The wide variety of clinical uses of albumin has been attributed to its following features1:
- Albumin has high nonimmunogenicity, biocompatibility, biodegradability and safety for its clinical application
- Albumin interacts with a range of drugs, potentially protecting them from metabolism and elimination, thus enhancing their pharmacokinetic properties
- Albumin can interact with receptors that are overexpressed in diseased cells and tissues, actively targeting disease sites without the need for specific ligands being added to the nanocarrier
In the clinic, albumin is administered intravenously, with a number of formulations available. The 5% formulation is more commonly used for volume loss caused by dehydration, and the 25% concentration is typically administered for oncotic deficiencies or when sodium or fluid is restricted11.
Examples of evidence-based clinical uses of albumin (5% and/or 25%)9:
- Acute nephrosis
- Adult respiratory distress syndrome (ARDS)
- Cardiopulmonary bypass procedures
- Hypoalbuminaemia
- Hypovolaemia
- Ovarian hyperstimulation syndrome
- Neonatal hyperbilirubinaemia
- Plasma exchange
- Prevention of central volume depletion after paracentesis from cirrhotic ascites
Albumin as fluid therapy
Clinically, albumin solutions have been used as plasma expanders and as volume replacement6 and therapeutic albumin has been administered in a range of diseases for decades, demonstrating safety in people who are critically ill12. Figure 4 illustrates how albumin is used in therapeutic plasma exchange.
Figure 4: The role of albumin in therapeutic plasma exchange (Adapted9).
The first use of HAS as a therapeutic agent occurred approximately 80 years ago, when it was administered to a young adult with traumatic shock9. Since then, albumin has been used in a range of clinical applications including burns, gastrointestinal and other internal bleeding, hypovolaemia, cardiopulmonary bypass, prevention of central volume depletion following paracentesis, and hypoalbuminaemia, including therapeutic plasmapheresis9.
Albumin use in drug and vaccine delivery
Thanks to its long half-life and being nonimmunogenic, HAS is used in drug delivery1. This is achieved either by covalent binding or noncovalent interaction1, noncovalent being generally preferred because of its reversibility, which allows for drugs to be released where required1.
Nanoparticle albumin-bound (NAB)-technology is one of the most popular drug-delivery systems that involve albumin1. It is nanotechnology-based and leverages the properties of albumin to deliver hydrophobic drugs selectively and efficiently without the use of toxic solvents1. This system has been considered a breakthrough technology, given that many chemotherapeutics are hydrophobic, which has traditionally presented challenges1. Nab-paclitaxel was created using NAB technology, and was approved by the US Food and Drug Administration (FDA) in 20051. It consists of albumin-based nanoparticles loaded with paclitaxel and is used to treat bladder cancer, gastric cancer (in Japan), non-small cell lung cancer, metastatic breast cancer, and metastatic adenocarcinoma of the pancreas1. Being a versatile carrier and able to bind numerous different drugs, other albumin-based nanoparticles have been developed for a range of indications and utilising a variety of binding strategies1.
Albumin may also have a role in vaccine delivery. For a vaccine to be efficient, the antigen must reach the lymph nodes and activate the innate and adaptive immune systems1. Albumin’s molecular weight of about 67 kDa may prevent antigen from being disseminated into the blood, thereby allowing it to be taken to the lymphatics where it accumulates, leading to greater immunogenicity than the equivalent soluble antigen can achieve1. Researchers hypothesise that nanovaccines could be created by combining exogenous molecular vaccines and endogenous nanocarriers such as albumin, to improve lymph node vaccine bioavailability and for enhanced immune response1.
Albumin’s affinity for particular receptors on epithelial and other cell surfaces in diseased organs allows for recognition and active targeting of the albumin-based formulation. Its versatility in carrying drugs could be extended to applications in imaging and gene therapy1.
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