Article Title

Tissue distribution of intravenously administrated poly-arginine peptide R18D in healthy male Sprague–Dawley rats


Aim: R18D is a poly-arginine peptide that has demonstrated neuroprotection in preclinical models of excitotoxicity, stroke, hypoxic-ischemic encephalopathy and traumatic brain injury. Here, we examined the peptide’s uptake in serum.

Materials & methods: Healthy, male Sprague–Dawley rats were intravenously administered either 1000 nmol/kg R18D (D-enantiomer of R18) or approximately 2.5 nmol/kg (36 ± 9 MBq) [18F]R18D, for serum and organ tissue uptake, respectively. Serum samples underwent mass spectrometric analysis to detect unbound R18D peptide. Animals administered [18F]R18D were subjected to positron emission tomography imaging.

Results & conclusion: Free R18D was detected at 5 min post-infusion in serum samples. [18F]R18D was rapidly distributed to the kidney (6–7%ID/g), and a small fraction localized to the brain (0.115–0.123%ID/g) over a 60-min acquisition period.

Lay abstract

R18D is a promising treatment for brain injury that has shown it can protect brain cells from damage in laboratory models of injury. These positive findings led us to examine what happens to R18D after administration in the body. Healthy, male rats were given 1000 nmol/kg R18D or approximately 2.5 nmol/kg (36 ± 9 MBq) [18F]R18D via an injection. Chemical and imaging analyses measured the amount of each compound. Free R18D was present in the blood 5 min after administration and was quickly absorbed by the kidney (6–7%ID/g) and brain (0.115–0.123%ID/g) within 60 min. Peptide-based therapies have been extensively explored due to their unique characteristics and potential for use following neurological injury. For example, cationic arginine-rich peptides (CARPs), such as the HIV-derived TAT, poly-arginine-9 and penetratin have been exploited in drug development for their cell-penetrating properties [13]. Not only are CARPs useful as carrier molecules for drug delivery, but they also possess intrinsic neuroprotective properties [4]. Studies from our laboratory have confirmed that the overall cationic change, and specifically the arginine content, are critical elements for CARP neuroprotective effects [57]. As a result of in vitro and in vivo neuroprotection studies using CARPs in different injury models, we have identified poly-arginine-18 (R18; 18-mer of arginine) as a leading therapeutic neuroprotective peptide [6].

Assessment of R18 and/or its D-enantiomer, R18D, in neuroprotection include studies using in vitro models of excitotoxicity and animal models of stroke, hypoxic-ischemic encephalopathy and traumatic brain injury [815]. However, despite the positive neuroprotection studies, the pharmacokinetic properties and systemic distribution of the R18 peptide have not been examined. Therefore, the aim of this study was to undertake a serum uptake and whole-body distribution study of R18 when administrated intravenously to healthy Sprague–Dawley rats. For the study, we decided to use R18D, as peptides synthesized with D-amino acids (i.e., D-arginine) are known to be more resistant to proteolytic degradation than peptides synthesized with naturally occurring L-amino acids.


Cationic arginine-rich peptides, iTRAQ, PET imaging, Pharmacokinetics, Poly-arginine, R18D

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