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