Biodistribution and pharmacokinetics of 188Re-liposomes and their comparative therapeutic efficacy with 5-fluorouracil in C26 colonic peritoneal carcinomatosis mice

Abstract

Background Nanoliposomes are designed as carriers capable of packaging drugs through passive targeting tumor sites by enhanced permeability and retention (EPR) effects. In the present study the biodistribution, pharmacokinetics, micro single-photon emission computed tomography (micro-SPECT/CT) image, dosimetry, and therapeutic efficacy of 188 Re-labeled nanoliposomes ( 188 Re-liposomes) in a C26 colonic peritoneal carcinomatosis mouse model were evaluated. Methods Colon carcinoma peritoneal metastatic BALB/c mice were intravenously administered 188 Re-liposomes. Biodistribution and micro-SPECT/CT imaging were performed to determine the drug profile and targeting efficiency of 188 Re-liposomes. Pharmacokinetics study was described by a noncompartmental model. The OLINDA|EXM ® computer program was used for the dosimetry evaluation. For therapeutic efficacy, the survival, tumor, and ascites inhibition of mice after treatment with 188 Re-liposomes and 5-fluorouracil (5-FU), respectively, were evaluated and compared. Results In biodistribution, the highest uptake of 188 Re-liposomes in tumor tissues (7.91% ± 2.02% of the injected dose per gram of tissue [%ID/g]) and a high tumor to muscle ratio (25.8 ± 6.1) were observed at 24 hours after intravenous administration. The pharmacokinetics of 188 Re-liposomes showed high circulation time and high bioavailability (mean residence time [MRT] = 19.2 hours, area under the curve [AUC] = 820.4%ID/g*h). Micro-SPECT/CT imaging of 188 Re-liposomes showed a high uptake and targeting in ascites, liver, spleen, and tumor. The results were correlated with images from autoradiography and biodistribution data. Dosimetry study revealed that the 188 Re-liposomes did not cause high absorbed doses in normal tissue but did in small tumors. Radiotherapeutics with 188 Re-liposomes provided better survival time (increased by 34.6% of life span; P < 0.05), tumor and ascites inhibition (decreased by 63.4% and 83.3% at 7 days after treatment; P < 0.05) in mice compared with chemotherapeutics of 5-fluorouracil (5-FU). Conclusion The use of 188 Re-liposomes for passively targeted tumor therapy had greater therapeutic effect than the currently clinically applied chemotherapeutics drug 5-FU in a colonic peritoneal carcinomatosis mouse model. This result suggests that 188 Re-liposomes have potential benefit and are safe in treating peritoneal carcinomatasis of colon cancer.

Colorectal Peritoneal Metastases: A Systematic Review of Current and Emerging Trends in Clinical and Translational Research

“…Eight papers were identified exploring the use of drug-eluting beads (drug loading vessels that can prolong drug release) [53] and nanoparticles, nanoliposomes, microspheres, or micelles (which increase drug specificity by being internalized by tumour cells) [43, 47, 57, 63, 70–72]. Intraperitoneally placed doxorubicin and mitoxenone drug-eluting beads were shown to continuously release the drug in lower concentrations decreasing side effects and mortality [53] with a similar decline in tumour load compared to free drug.…”

“…Due to enhanced permeability and retention in tumour cells, nanoliposomes can achieve selective uptake by tumour cells, increasing antitumour efficacy whilst minimising collateral side effects [73]. In one study, it was found that drug delivery using IV 188Re-liposomes increased survival by 34% ( p < 0.05) and decreased tumour volume and ascites by 63.4% and 83.3%, respectively, at 7 days after treatment in mice ( p < 0.05) [70]. In 2007, a phase I study using PLC (doxorubicin encapsulated in liposomes) as part of the HIPEC regime in 29 patients found nanoliposomes to be well tolerated, resulting in a more favourable side effect profile and overall survival of 30.6 months [72].…”

<p>¹³¹I-labeled polyethylenimine-entrapped gold nanoparticles for targeted tumor SPECT/CT imaging and radionuclide therapy</p>

“…Single-photon emission computed tomography (SPECT), one of the most important radionuclide-based imaging techniques, has shown great value in tumor imaging 11–14. Meanwhile, a number of therapeutic radionuclides have been widely used for tumor treatment, including but not limited to iodine-131 ( 131 I), rhenium-188 ( 188 Re), yttrium-90 ( 90 Y), lutetium-177 ( 177 Lu), and radium-223 ( 223 Ra) 15–21. Among these therapeutic radionuclides, 131 I has been routinely used in radionuclide therapy and imaging of thyroid diseases, such as thyroid cancer, because of its high affinity for the thyroid and relatively long half-life (8.01 days).…”

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

“…Various tumor models consistently demonstrate the therapeutic and synergistic combination effects of 188 Re-liposome with chemotherapeutics, including subcutaneously inoculated murine CT26 [28, 31], human LS-174 T [30], and a murine C26 colon carcinoma ascites model [27, 29]. Tumor growth is suppressed, survival time is increased [27, 29, 32], and there is a synergistic chemo/radiotherapeutic [28] effect in various tumor-bearing mice. 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].…”

“…Tumor growth is suppressed, survival time is increased [27, 29, 32], and there is a synergistic chemo/radiotherapeutic [28] effect in various tumor-bearing mice. 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].…”