Pharmacokinetics, biodistribution and toxicology of novel cell-penetrating peptides

Abstract

Cell-penetrating peptides (CPPs) have been used in basic and preclinical research in the past 30 years to facilitate drug delivery into target cells. However, translation toward the clinic has not been successful so far. Here, we studied the pharmacokinetic (PK) and biodistribution profiles of Shuttle cell-penetrating peptides (S-CPP) in rodents, combined or not with an immunoglobulin G (IgG) cargo. We compared two enantiomers of S-CPP that contain both a protein transduction domain and an endosomal escape domain, with previously shown capacity for cytoplasmic delivery. The plasma concentration versus time curve of both radiolabelled S-CPPs required a two-compartment PK analytical model, which showed a fast distribution phase (t1/2α ranging from 1.25 to 3 min) followed by a slower elimination phase (t1/2β ranging from 5 to 15 h) after intravenous injection. Cargo IgG combined to S-CPPs displayed longer elimination half-life, of up to 25 h. The fast decrease in plasma concentration of S-CPPs was associated with an accumulation in target organs assessed at 1 and 5 h post-injection, particularly in the liver. In addition, in situ cerebral perfusion (ISCP) of L-S-CPP yielded a brain uptake coefficient of 7.2 ± 1.1 µl g−1 s−1, consistent with penetration across the blood–brain barrier (BBB), without damaging its integrity in vivo. No sign of peripheral toxicity was detected either by examining hematologic and biochemical blood parameters, or by measuring cytokine levels in plasma. In conclusion, S-CPPs are promising non-toxic transport vectors for improved tissue distribution of drug cargos in vivo.

Toxicity Studies of Cardiac-Targeting Peptide Reveal a Robust Safety Profile

“…Our results with CTP are consistent with reports in the literature on other CPPs [ 45 , 46 , 47 ]. Obviously, the toxicity profile will vary from one peptide to the next, and depend on the dose tested.…”

Bioavailability and Metabolism of Bioactive Peptide IRW with Angiotensin-Converting Enzyme 2 (ACE2) Upregulatory Activity in Spontaneously Hypertensive Rats

“…Consequently, the time zero data for calculating the AUC (0−t) for the injection were extrapolated, using the y-intercept of the regression formula derived from measured data, akin to a method employed in a previous report. 49 This step would prevent overestimating the bioavailability of IRW. Collectively, future studies assessing the bioavailability of compounds should incorporate both male and female rats to achieve a more comprehensive evaluation and should collect time zero data for more accurate results.…”

“…In addition, in this current investigation of bioavailability, time zero concentration data ( t 0 ) for injection were not directly obtained. Consequently, the time zero data for calculating the AUC (0– t ) for the injection were extrapolated, using the y-intercept of the regression formula derived from measured data, akin to a method employed in a previous report . This step would prevent overestimating the bioavailability of IRW.…”

Peptide-Hitchhiking for the Development of Nanosystems in Glioblastoma

“…The clinical potential of CPPs for drug delivery may also be hampered by the rapid clearance through the reticuloendothelial system due to the cationic nature of these peptides. This limitation significantly impacts the efficacy of CPPs, as it can result in low bioavailability and poor uptake into target cells. − …”