A Kidney‐targeted Protein Biopolymer Drug Delivery System

Abstract

Elastin-like Polypeptides (ELPs) are bioengineered protein polymers that can be used as drug carriers. ELPs are composed of a repeating pentapeptide motif, their sequence is genetically encoded, and they are produced by recombinant expression in E. coli. Simple molecular biology strategies are used to change the number of pentapeptide repeats to tune the polymer's size and to modify the sequence's N- and C-termini to add targeting peptides and therapeutic peptides, therapeutic proteins, or reactive sites for drug conjugation. In addition to its amenability to sequence modification, ELP is a thermally responsive biopolymer. It self-associates into aggregates above a user defined transition temperature, and the aggregation process is fully reversible. This allows ELP and ELP-fusion proteins to be purified using simple thermal precipitation. We previously showed that ELP has a high affinity for the kidney when administered by systemic injection. Here, we assessed the ability of targeting peptides to increase the kidney binding and kidney specificity. Two non-organ specific cell penetrating peptides (Tat and SynB1) and one renal-specific kidney targeting peptide (KTP) were fused to ELP, and their pharmacokinetics and biodistribution were determined using quantitative fluorescence measurements in a rat model. All three peptides increased kidney deposition of ELP by over four-fold (p < 0.0001), but the KTP was the most specific for the kidney, achieving targeting levels of 15-fold when comparing kidney:liver ratios and 150-fold when comparing kidney:heart ratios. This research was supported by NIH grant R01HL121527 to GLB and NIH grant R01HL095638 and AHA grant 18490005 to ARC.