Albumin: the next-generation delivery technology.

Abstract

Motivation for next-generation delivery technology The therapeutic efficacy of a drug is determined by the ability for site-specific engagement with its biological target. A poor pharmacokinetic profile as a result of degradation, rapid renal clearance or nonspecific accumulation requires enabling technologies provided by delivery science. Two major delivery branches are plasma half-life extension for improved stability and prolonged plasma residence time for long-acting extracellular drugs, and targeted intracellular drug-delivery to maximize organ-specific or intracellular drug-delivery. Poly (ethylene glycol) (PEG) conjugation, termed PEGylation [1], is the standard and predominant technology to improve solubility, stability and extend plasma half-life of peptide and protein-based drugs. PEGylation has been a highly successful approach demonstrated by an array of marketed products such as Adagen (PEG-adenosine deaminase [Enzon]) and Pegasys (PEG-IFN alpha-2α [Pegasys]) [2]. PEGylation, however, has drawbacks such as a need for chemical conjugation, tissue accumulation of high molecular weight PEG, and, possible reduction in efficacy and nonfavored altered drug biodistribution. From its conception from early macro and microscale systems for the controlled release of drugs, current advanced drug-delivery systems such as lipid and polymer-based nanocarriers have the capacity for temporal and spatial control of drug delivery. Exploitation of the unique properties occurring at the nanoscale has given rise to the field of ‘nanomedicine’ that offers great promise in the future. Nanocarrier capture by the cellular components of the mononuclear phagocyte system, immunogenicity and nonspecific tissue accumulation, however, requires surface engineering to install stealth and targeting properties. The lack of novel targeting ligands combined with elaborate design necessity and possible toxicity restricts a rapid translation into the clinic. It is clear there is a need for next-generation half-life extension and targeted drug-delivery technologies that are simple in design, biodegradable and nonimmunogenic. Human serum albumin (HSA) may provide the solution to this unmet challenge. Albumin is a natural carrier protein possessing multiple ligand binding sites and a plasma half-life of approximately 20 days [3] facilitated by engagement with the endothelial and epithelial cellular recycling neonatal Fc receptor (FcRn) [4], and megalin-cubilin receptor-mediated renal rescue [5] affording a broad biodistribution and tissue penetration in normal and disease conditions. Utilization of its physiological transport mechanisms and its high charge and solubility properties, promotes albumin as a highly attractive technology that can be utilized for both half-life extension and targeted intracellular delivery applications. Its key role in ligand-binding transport for biomolecules, for example, fatty acids has been exploited in the design of albumin-binding drugs such as insulin analog detemir (Levemir) [6] and Albumin: the next-generation delivery technology