Therapeutic efficacy and microSPECT/CT imaging of 188Re-DXR-liposome in a C26 murine colon carcinoma solid tumor model

https://doi.org/10.1016/j.nucmedbio.2009.08.006Get rights and content

Abstract

Nanocarriers can selectively target cancer sites and carry payloads, thereby improving diagnostic and therapeutic effectiveness and reducing toxicity. The objective of this study was to investigate the therapeutic efficacy of a new co-delivery radiochemotherapeutics of 188Re-N,N-bis (2-mercaptoethyl)-N′,N′-diethylethylenediamine (BMEDA)-labeled pegylated liposomal doxorubicin (DXR) (188Re-DXR-liposome) in a C26 murine colon carcinoma solid tumor model. To evaluate the targeting and localization of 188Re-DXR-liposome in C26 murine tumor-bearing mice, biodistribution, microSPECT/CT imaging and pharmacokinetic studies were performed. The antitumor effect of 188Re-DXR-liposome was assessed by tumor growth inhibition, survival ratio and histopathological hematoxylin–eosin staining. The tumor target and localization of the nanoliposome delivery radiochemotherapeutics of 188Re-DXR-liposome were demonstrated in the biodistribution, pharmacokinetics and in vivo nuclear imaging studies. In the study on therapeutic efficacy, the tumor-bearing mice treated with bimodality radiochemotherapeutics of 188Re-DXR-liposome showed better mean tumor growth inhibition rate (MGI) and longer median survival time (MGI=0.048; 74 days) than those treated with radiotherapeutics of 188Re-liposome (MGI=0.134; 60 days) and chemotherapeutics of Lipo-Dox (MGI=0.413; 38 days). The synergistic tumor regression effect was observed with the combination index (CI) exceeding 1 (CI=1.145) for co-delivery radiochemotherapeutics of 188Re-DXR-liposome. Two (25%) of the mice treated with radiochemotherapeutics were completely cured after 120 days. The therapeutic efficacy of radiotherapeutics of 188Re-liposome and the synergistic effect of the combination radiochemotherapeutics of 188Re-DXR-liposome have been demonstrated in a C26 murine solid tumor animal model, which pointed to the potential benefit and promise of the co-delivery of nanoliposome radiochemotherapeutics for adjuvant cancer treatment on oncology applications.

Introduction

Currently, applying nanocarriers for strengthening cancer diagnostics and therapeutics poses emerging opportunities and challenges [1], [2], [3], [4], in particular, passive and active nanocarriers [2], [3]. Liposomal drugs such as pegylated liposomal doxorubicin (DXR) can be designed to improve the pharmacological and therapeutic index for cancer therapeutics [4], [5], but the limited distribution of doxorubicin in solid tumors causes drug resistance and lower chemotherapy response [6]. The developments for improving therapeutic efficacy, reducing side effects and overcoming the drug resistance of multiplex nanoliposomes are of considerable interest [2], [3], [4], [5].

Internal radiotherapy with nanoliposome (100-nm range) delivery of radionuclide or chemotherapeutic payloads can be selectively targeted to tumor while reducing nonspecific accumulation [7]. Rhenium-188 emits a 155-keV gamma photon and a 2.12-MeV beta particle suitable for nuclear imaging and targeted radionuclide therapy. We have studied the biodistribution, pharmacokinetics and SPECT/CT imaging investigations by intraperitoneal and intravenous administration of 188Re-liposome in C26 colon carcinoma ascites and solid tumor animal models [8], [9]. However, the therapeutic applications of new radiotherapeutics of 188Re-liposome and combination radiochemotherapeutics of 188Re-DXR-liposome in malignant solid tumor-bearing animal model have not been reported yet.

In this study, a new combination of bimodality radiochemotherapeutics was designed and studied for treating solid colon tumor by intravenous administration. The biodistribution, pharmacokinetics and in vivo nuclear images of tumor, prolonged survival time and therapeutic efficacy of radiochemotherapeutics of 188Re-DXR-liposome were evaluated in C26 malignant colon solid tumor-bearing mice.

Section snippets

Materials

Distearoylphosphatidylcholine (DSPC), cholesterol and polyethylene glycol (average molecular weight: 2000)-derived distearoylphosphatidylethanolamine (PEG-DSPE) were purchased from Avanti Polar Lipids (Alabaster, AL, USA). 188Re was obtained from an in-house 188W/188Re generator. Cell culture reagents were obtained from GIBCO BRL (Grand Island, NY, USA). N,N-bis(2-Mercaptoethyl)-N',N'-diethylethylenediamine (BMEDA) was purchased from ABX (Radeberg, Germany). Stannous chloride (SnCl2) was

Labeling efficiency and in vitro stability of 188Re-DXR-liposome

The labeling efficiency of 188Re-BMEDA was greater than 95%. The encapsulation efficiency of 188Re-BMEDA in pegylated nanoliposomes and Lipo-Dox was 81.4±4.3% and 73.1±8.5% (n=5), respectively. The radiochemical purity of 188Re-liposome and 188Re-DXR-liposome was both higher than 95%. The in vitro stability of 188Re-DXR-liposome after incubating with rat plasma at 37°C for 72 h was 63.5±0.6% (mean±S.D; n=3). 188Re-DXR-liposomes showed less in vitro stability in rat plasma than 188Re-liposomes

Discussion

In our previous studies, the results of biodistribution, pharmacokinetics and micro SPECT/CT imaging demonstrated the benefits of passive radiotherapeutics of 188Re-liposome in C26 colon carcinoma ascities and solid tumor animal models [8], [9]. In this investigation, the doxorubicin-less sensitive murine C26 colon carcinoma model was chosen for studying and comparing the therapeutic efficacy and antitumor effect of a new bimodality radiochemotherapeutic combination treatment [20].

Nuclear

Conclusion

The tumor targeting and localization of the new passive co-delivery multifunctional radiochemotherapeutics of 188Re-DXR-liposomes were confirmed by biodistribution, pharmacokinetics and in vivo microSPECT/CT imaging. The therapeutic efficacy of the 188Re-liposome and 188Re-DXR-liposome was noted on the C26 colon carcinoma solid tumor mice model. The synergistic therapeutic efficacy was demonstrated for the new combination therapies of 188Re-DXR-liposome. The results of this therapeutic efficacy

Acknowledgments

The authors would like to thank W.C. Lee, C.L. Ho, W.C. Hsu, C.H. Yeh and Y.H. Wu for their assistance in the experiment, and C.J. Liu for his help with the preparation of 188Re.

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    Y.-J. Chang and C-H. Chang contributed equally to this paper.

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