Elsevier

Journal of Controlled Release

Volume 132, Issue 3, 18 December 2008, Pages 171-183
Journal of Controlled Release

Albumin as a drug carrier: Design of prodrugs, drug conjugates and nanoparticles

https://doi.org/10.1016/j.jconrel.2008.05.010Get rights and content

Abstract

Albumin is playing an increasing role as a drug carrier in the clinical setting. Principally, three drug delivery technologies can be distinguished: coupling of low-molecular weight drugs to exogenous or endogenous albumin, conjugation with bioactive proteins and encapsulation of drugs into albumin nanoparticles.

The accumulation of albumin in solid tumors forms the rationale for developing albumin-based drug delivery systems for tumor targeting. Clinically, a methotrexate-albumin conjugate, an albumin-binding prodrug of doxorubicin, i.e. the (6-maleimido)caproylhydrazone derivative of doxorubicin (DOXO-EMCH), and an albumin paclitaxel nanoparticle (Abraxane) have been evaluated clinically. Abraxane has been approved for treating metastatic breast cancer.

An alternative strategy is to bind a therapeutic peptide or protein covalently or physically to albumin to enhance its stability and half-life. This approach has been applied to peptides with antinociceptive, antidiabetes, antitumor or antiviral activity: Levemir, a myristic acid derivative of insulin that binds to the fatty acid binding sites of circulating albumin, has been approved for the treatment of diabetes. Furthermore, Albuferon, a fusion protein of albumin and interferon, is currently being assessed in phase III clinical trials for the treatment of hepatitis C and could become an alternative to pegylated interferon. This review gives an account of the different drug delivery systems which make use of albumin as a drug carrier with a focus on those systems that have reached an advanced stage of preclinical evaluation or that have entered clinical trials.

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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