Albumin as a drug carrier: Design of prodrugs, drug conjugates and nanoparticles
Introduction
Albumin is emerging as a versatile protein carrier for drug targeting and for improving the pharmacokinetic profile of peptide- or protein-based drugs. Albumin is the most abundant plasma protein (35–50 g/L human serum) with a molecular weight of 66.5 kDa. Like most of the plasma proteins, albumin is synthesized in the liver where it is produced at a rate of approximately 0.7 mg/h for every gram of liver (i.e. 10–15 g daily); Human serum albumin (HSA) exhibits an average half-life of 19 days. The functions and binding properties of HSA are multifold [1]: a) it acts as the solubilizing agent for long chain fatty acids and is therefore essential for the metabolism of lipids; b) it binds bilirubin, the breakdown product of heme; c) it binds a great number of therapeutic drugs such as penicillins, sulfonamides, indole compounds, and benzodiazepines to name just a few; d) it binds copper(II) and nickel(II) in a specific and calcium(II) and zinc(II) in a relatively nonspecific manner and acts as the transport vehicle for these metal ions in the blood; e) it is the major protein responsible for the colloid osmotic pressure of the blood; f) when HSA is broken down, the amino acids provide nutrition to peripheral tissue.
The three-dimensional structure of HSA has been elucidated by X-ray structure analysis [2], [3]. The approximate three-dimensional shape of HSA can be described as an ellipsoid consisting of three flexible spheres in a row (domains I, II, III) and is illustrated schematically in Fig. 1. HSA is one of the smallest proteins present in blood plasma. Both size and abundance explain the fact that so many metabolic compounds and therapeutic drugs are transported by this protein. The binding sites for metabolic substrates and diagnostic as well as therapeutic drugs have been extensively studied and reviewed [4], [5].
HSA is used for treating shock, burns, hypoalbuminemia, surgery or trauma, cardiopulmonary bypass, acute respiratory distress and hemodialysis [6]. As an alternative to blood derived albumin, recombinant human serum albumin (Recombumin) has been developed and is a genetically engineered protein expressed in yeast cells that has shown comparable safety, tolerability, pharmacokinetics and pharmacaodynamics to native HSA [7].
Albumin is an acidic, very soluble protein that is extremely robust: it is stable in the pH range of 4–9, soluble in 40% ethanol, and can be heated at 60 °C for up to 10 h without deleterious effects. These properties as well as its preferential uptake in tumor and inflamed tissue, its ready availability, its biodegradability, and its lack of toxicity and immunogenicity make it an ideal candidate for drug delivery.
This review gives an account of the different drug delivery systems that make use of albumin as a drug carrier that encompass drug conjugates, drug adducts, albumin-binding derivatives and nanoparticles.
Section snippets
Albumin as a drug carrier
Albumin accumulates in malignant and inflamed tissue due to a leaky capillary combined with an absent or defective lymphatic drainage system. Tumor uptake in preclinical models can be easily visualized by injecting the dye evans blue that binds rapidly and tightly to circulating albumin and makes subcutaneously growing tumors turn blue within a few hours post-injection (see Fig. 2). As an alternative to drug targeting, conjugating therapeutic peptides or cytokines with albumin is an attractive
Drug albumin conjugates and albumin-binding drug derivatives
Historically, the first drug albumin conjugates were synthesized by direct coupling methods followed by the development of albumin-binding peptides and prodrugs that bind rapidly and selectively to the cysteine-34 position of exogenous and endogenous albumin [23], [26]. In addition, drug albumin conjugates that contain an appropriate ligand for receptor targeting such as sugars [27] or RGD peptides [28] for application in liver and vascular targeting have been developed. In the diagnostic
Albumin microspheres
Albumin microspheres are generally prepared by chemical cross-linking or by addition of an organic solvent and stabilization at elevated temperatures. The size of the albumin microspheres which is usually in the range of 1–100 μm is the decisive factor for the biodistribution characteristics of the albumin microsphere. Small microspheres (1–3 μm are taken up by the reticuloendothelial system and accumulate in the liver and spleen as well as in solid tumors. Larger microspheres (> 15 μm) will
Summary and outlook
Albumin is the chief circulating protein in the blood circulation and a transport protein per se for a number of endogenous and exogenous compounds. For the protein chemist, albumin is not a standard protein since it is extremely robust towards pH, temperature and organic solvents and can be stored as a 5 or 20% solution for many years. The different uses of albumin as a drug carrier that have emerged in the past 10 years are fascinating and range from extending the half-life of therapeutically
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