Extended acute toxicity study of ¹⁸⁸Re‐liposome in Rats

Abstract

Liposomes can selectively target cancer sites and carry payloads, thereby improving diagnostic and therapeutic effectiveness as well as reducing toxicity. To evaluate therapeutic strategies, it is essential to use animal models reflecting important safety aspects before clinical application. As our previous study found that a high dosage (185 of MBq) of (188) Re-N,N-bis (2-mercaptoethyl)-N',N'-diethylethylenediamine-labeled pegylated liposomes ((188) Re-liposome) induced a decrease in white blood cell (WBC) count in Sprague-Dawley rats 7 days postinjection, the objective of the present study was to investigate extended acute radiotoxicity of (188) Re-liposome. Rats were administered via intravenous (i.v.) injection with (188) Re-liposome (185, 55.5 and 18.5 MBq), normal saline as a blank control or non-radioactive liposome as a vehicle control. Mortality, clinical signs, food consumption, body weights, urinary, biochemical and hematological analyzes were examined. In addition, gross necropsy and histopathological examinations were also performed at the end of the follow-up period. None of the rats died and no clinical sign was observed during the 28-day study period. Only male rats receiving (188) Re-liposome at a high dosage (185 MBq) displayed a slight weight loss compared with the control rats. In both male and female rats, the WBC counts of both high-dose and medium-dose (55.5 MBq) groups reduced significantly 7 days postinjection, but recovered to the normal range on Study Day 29. There was no significant difference in urinary analyzes, biochemical parameters and histopathological assessments between the (188) Re-liposome-treated and control groups. The information generated from the present study on extended acute toxicity of (188) Re-liposome will serve as a safety reference for radiopharmaceuticals in early-phase clinical trials.

Involvement of let-7 microRNA for the therapeutic effects of Rhenium-188-embedded liposomal nanoparticles on orthotopic human head and neck cancer model

“…An earlier study revealed that no significant changes in WBC counts were noticed between 188 Re-liposome and normal saline-treated mice, suggesting no apparent hematotoxicity in 188 Re-liposome treatment [ 36 ]. Furthermore, it has been reported that in normal murine, 188 Re-liposome did not raise significant death or clinical signs after intravenous injection from 18.5 MBq to 185 MBq [ 37 ]. Because only 1.85 MBq was used for tumor-bearing mice in this study, it is speculated that the toxicity of 188 Re-liposome would be low and acceptable for therapy.…”

Radiopharmaceutical enhancement by drug delivery systems: A review

“…No severe toxicity was demonstrated in the selected rodent models. High dosages were associated with short term weight-loss, a temporary reduction in haematological parameters and a cytogenetic risk [65,66]. Synergistic enhancement of the efficacy of this system is reported with concomitant administration of doxorubicin liposomes as well as external beam radiotherapy [67,68].…”

A phase 0 study of the pharmacokinetics, biodistribution, and dosimetry of 188Re-liposome in patients with metastatic tumors

“…The efficacy of 188 Re-liposome as a nano-targeted radiotherapeutic has been demonstrated to be greater than that of the chemotherapeutics, Lipo-Dox [27, 28], 5-FU [29–31], and sorafenib [32]. Preclinical toxicity studies did not show any discernible toxicity in either mice [31] or rats [33, 34]. The encouraging data for the targeting of animal tumors, pharmacokinetics, biodistribution, dosimetric evaluation, preclinical efficacy, and toxicity resulted in a phase 0 low radioactivity human clinical trial to determine the potential of 188 Re-liposome as a new passive nano-targeted anti-cancer radiotherapeutic.…”