Preliminary evaluation of acute toxicity of ¹⁸⁸Re–BMEDA–liposome in rats

Abstract

Liposomes can selectively target cancer sites and carry payloads, thereby improving diagnostic and therapeutic effectiveness and reducing toxicity. To evaluate therapeutic strategies, it is essential to use animal models reflecting important safety aspects before clinical application. The objective of this study was to investigate acute radiotoxicity of ¹⁸⁸Re-N,N-bis (2-mercaptoethyl)-N',N'-diethylethylenediamine (BMEDA)-labeled pegylated liposomes (¹⁸⁸Re-BMEDA-liposome) in Sprague-Dawley rats. Rats were administered with ¹⁸⁸Re-BMEDA-liposome, normal saline as blank or non-radioactive liposome as vehicle control via intravenous injection and observed for 14 days. Examinations were conducted with respect to mortality, clinical signs, food consumption, body weight and hematological and biochemical analyses. In addition, gross necropsy, histopathological examinations and cytogenetic analyses were also performed. None of the rats died and no clinical sign was observed during the 14-day study period. Rats administered with ¹⁸⁸Re-BMEDA-liposome at dosage of 185 MBq displayed a significant weight loss compared with the control from study day (SD) 1 to SD 4, and the white blood cell count reduced to 5-10% of initial value (female: 18.55 ± 6.58 to 0.73 ± 0.26 x 10³ µl⁻¹; male: 14.52 ± 5.12 to 1.43 ± 0.54 x 10³ µl⁻¹) 7 days-post injection, but were found to have recovered on SD 15. There were no significant differences in biochemical parameters and histopathological assessments between the ¹⁸⁸Re-BMEDA-liposome-treated and control groups. The frequencies of dicentric chromosomes were associated with dosage of ¹⁸⁸Re-BMEDA-liposome. The information generated from this study on acute toxicity will serve as a safety reference for further subacute toxicity study in rats and human clinical trials.

Chemoradionuclide Therapy with186Re-Labeled Liposomal Doxorubicin: Toxicity, Dosimetry, and Therapeutic Response

“…The toxicity observed was similar to that reported for 188 Re-BMEDA-liposomes. 28 Kidneys are radiosensitive…”

“…26,27 A significant theoretical advantage was the low dose delivered to the bone marrow for radiolabeled liposomes compared with radiolabeled antibodies. 26,27 Preclinical studies of 188 Re-liposomes have also shown the acute toxicity 28 and potential of this therapy in colon carcinoma. [29][30][31][32] A simple method of encapsulating rhenium radionuclides into liposomes and Doxil using N,N-bis(2-mercaptoethyl)-N¢,N¢-diethylethylenediamine (BMEDA) with high labeling efficiency and good stability has been reported.…”

Extended acute toxicity study of 188Re‐liposome in Rats

“…Our previous findings suggest that 188 Rhenium‐labeled pegylated liposomes ( 188 Re‐liposome) is a promising candidate for cancer therapy in C26 murine colon carcinoma ascites (Chang et al ., ; Chen et al ., , ) and a solid tumor model (Chang et al ., , , ). In addition, a 14‐day acute toxicity study was also performed to evaluate radiotoxicity of 188 Re‐liposome in rodents (Liu et al ., ). Although none of the rats died and no clinical sign was observed during the study period, rats administered with 185 MBq of 188 Re‐liposome displayed a significant decrease in white blood cell (WBC) counts 7 days postinjection.…”

Imaging, Autoradiography, and Biodistribution of188Re-Labeled PEGylated Nanoliposome in Orthotopic Glioma Bearing Rat Model

“…Moreover, the 188 Re-labeled liposome encapsulated with doxorubicin as a bimodal radiochemotherapeutic agent has been recently investigated in a series of translational studies for cancer treatment using animal models with colon cancer and related ascites. [16][17][18][19][20][21]25 In this current study, the 188 Re-BMEDA complexencapsulated neutral PEGylated liposomes (abbreviated as 188 Re-Liposome) was prepared and evaluated as a diagnostic and therapeutic agent for glioma. An orthotopic glioma tumor-bearing rat model (Fischer/F98) was prepared to mimic the behavior of human malignant astrocytomas for the study.…”