The Pharmacokinetics of Cell-Penetrating Peptides

Abstract

Cell-penetrating peptides (CPPs) are able to penetrate the cell membrane carrying cargoes such as peptides, proteins, oligonucleotides, siRNAs, radioisotopes, liposomes, and nanoparticles. Consequently, many delivery approaches have been developed to use CPPs as tools for drug delivery. However, until now a systematic analysis of their in vivo properties including potential tumor binding specificity for drug targeting purposes has not been conducted. Ten of the most commonly applied CPPs were obtained by solid phase peptide synthesis and labeled with (111)In or (68)Ga. Uptake studies were conducted using a panel of six tumor cell lines of different origin. The stability of the peptides was examined in human serum. Biodistribution experiments were conducted in nude mice bearing human prostate carcinoma. Finally, positron emission tomography (PET) measurements were performed in male Wistar rats. The in vitro uptake studies revealed high cellular uptake values, but no specificity toward any of the cell lines. The biodistribution in PC-3 tumor-bearing nude mice showed a high transient accumulation in well-perfused organs and a rapid clearance from the blood. All of the CPPs revealed a relatively low accumulation rate in the brain. The highest uptake values were observed in the liver (with a maximal uptake of 51 %ID/g observed for oligoarginine (R(9))) and the kidneys (with a maximal uptake of 94 %ID/g observed for NLS). The uptake values in the PC-3 tumor were low at all time points, indicating a lack of tumor specific accumulation for all peptides studied. A micro-PET imaging study with (68)Ga-labeled penetratin, Tat and transportan(10) (TP(10)) confirmed the organ distribution data. These data reveal that CPPs do not show evidence for application in tumor targeting purposes in vivo. However, CPPs readily penetrate into most organs and show rapid clearance from the circulation. The high uptake rates observed in vitro and the relatively low specificity in vivo imply that CPPs would be better suited for topical application in combination with cargoes which show passive targeting and dominate the pharmacokinetic behavior. In conclusion, CPPs are suitable as drug carriers for in vivo application provided that their pharmacokinetic properties are also considered in design of CPP drug delivery systems.

Transportan in nanocarriers improves skin localization and antitumor activity of paclitaxel

“…50,51 PTDs have been most frequently studied for systemic delivery, but the high in vitro uptake rates, the relatively low specificity, and the fast clearance rates observed in several studies suggest that their topical application presents a higher potential. 52,53 Our results support the potential of selected PTDs to improve drug topical delivery, leading to a more pronounced efficacy against a bioengineered model of melanoma. Given the fact that the PTDs were simply mixed into ME, their amphiphilic properties may play an important role as demonstrated by the stronger effect of ME-T compared to ME-TAT, at least within the experimental conditions used here.…”

Inhibition of the Multidrug Resistance P-Glycoprotein: Time for a Change of Strategy?

“…Typically, internalized particles will enter the endosomal pathway that leads to lysosomal degradation (Riezman et al, 1997;Wattiaux et al, 2000), which may result in irretrievable transformation or sequestration of the payload. A number of strategies have been adopted, including the use of cellpenetrating peptides (Sarko et al, 2010;Choi et al, 2011) or platforms containing drug tethers that are destabilized by the acidic intratumoral microenvironment (Andreev et al, 2010;Gao et al, 2010;Du et al, 2013).…”

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