Abstract
Elastin-like polypeptides (ELP) are engineered proteins that consist of repetitions of a five amino acid motif, and their composition is easily modified to adjust their physical properties and attach therapeutics. Because of the repetitive nature of the ELP sequence, polymer size is particularly amenable to manipulation. ELP fusion proteins are being actively developed as therapeutics for many disease applications, and how the ELP size and shape affects its pharmacokinetics and biodistribution is a critical question for the general field of ELP drug delivery. To address this, we generated a library of ELPs ranging in size from 25 kDa to 110 kDa. Terminal plasma half-life was directly proportional to polymer size, and organ biodistribution was also size dependent. The kidneys accumulated the highest levels of ELP of all sizes, followed by the liver. Within the kidney, most ELP was found in the proximal tubule, but intra-renal localization shifted from exclusively cortical to a mixture of cortical and medullary as ELP size increased.
Highlights
The Elastin-like polypeptides (ELP) sequence is modified to include therapeutic peptides and proteins, and small molecule drugs can be chemically attached
We showed that the ELP-vascular endothelial growth factor (VEGF) chimera maintains full potency in vitro and has improved pharmacokinetic parameters in vivo[17]
We aimed to define the effects of molecular weight on the pharmacokinetics, biodistribution, and renal deposition of ELP and to determine the molecular weight best suited for renal drug delivery
Summary
The ELP sequence is modified to include therapeutic peptides and proteins, and small molecule drugs can be chemically attached. ELPs can be engineered to form nanoparticles for specialized drug delivery applications or to form hydrogels for controlled drug release[20,21,22,23,24]. A study by Dreher et al investigated how molecular weight influences accumulation of a model macromolecular drug carrier, dextran, in tumors[26]. They found that an increase in the dextran MW significantly decreased their vascular permeability, yet it increased their plasma www.nature.com/scientificreports/. Beyond our specific application to renal drug delivery, this study provides a detailed characterization of how ELP chain length affects the protein’s pharmacokinetics and biodistribution, which is critical information when developing ELPs as drug carriers for many different disease applications
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