Biodistribution, pharmacokinetics and imaging of 188Re-BMEDA-labeled pegylated liposomes after intraperitoneal injection in a C26 colon carcinoma ascites mouse model
Introduction
Nanoliposomes are double-membrane lipid vesicles capable of packaging drugs for various delivery applications. Nanopegylated liposomes can evade the reticuloendothelial system (RES) and remain in the circulation for prolonged periods, resulting in sufficient tumor targeting and efficacy in animal models [1], [2]. Nanopegylated liposomes are provided with passive targeting because of nanoliposome accumulation in tumor by means of enhanced permeability and retention (EPR) effect through leaky tumor vasculature [1], [2], [3], [4]. Preclinical studies have shown that cytotoxic agents entrapped in pegylated liposomes tend to accumulate in tumors [5], [6]. Nowadays, pegylated liposomal doxorubicin have been applied in patients with AIDS-related Kaposi's sarcoma, ovarian, breast and prostate carcinomas [7].
Colorectal cancer is one of the most common types of cancer. Its prognosis depends on the extent of the disease [8]. Peritoneal spread is the terminal stage in colorectal cancer. The peritoneal carcinomatosis is the most common cause of malignant ascites; the production and leakage of fluid from the malignant cells causes exudation of extracellular fluid into peritoneal cavity [9]. Peritoneal carcinomatosis is one of the major causes of mortality in colorectal cancer patients [10], [11]. Malignant ascites is an abnormal buildup of fluid in the abdomen caused by tumor, which can cause discomfort, pain and symptoms that diminish the quality of life for cancer patients. Intraperitoneal (ip) administration of anticancer drugs is one of the valuable noninvasive strategies in the treatment of peritoneal malignant disease. The advantage of ip injection is that it delivers high doses of cytotoxic agents directly to the tumor sites while potentially reducing the toxicity of systemic drug administration [12]. Several clinical studies have suggested that ip chemotherapy would be very suitable in the adjuvant setting of colon cancer due to the route of spread of cancer cells [13]. Preclinical and clinical studies have described the use of ip chemotherapy with conventional and pegylated liposomes to such diseases as ovarian cancer, leukaemia and lymphoma [14], [15], [16]. In addition, pegylated liposomal doxorubicin is used in the therapy for peritoneal dissemination via ip administration [17].
Preclinical studies of tumor therapy with radionuclide–liposome conjugates or liposome-mediated radiopharmaceuticals have been reported [18], [19]. Intraperitoneal radionuclide therapy is a treatment method for treating systemic or metastatic malignant tumor in peritoneal cavity. Preclinical and clinical studies indicate some advantages for ip administration in the regional localization of small peritoneal metastases tumors [20], [21]. 188Re is a radionuclide for imaging and therapeutic dual applications due to its short physical half-life of 16.9 h with 155 keV gamma emission for imaging and its 2.12 MeV β emission with maximum tissue penetration range of 11 mm for tumor therapeutics [22]. In addition, 188Re can be obtained from a generator, which makes it convenient for routine research and clinical use.
Although the 186Re-N,N-bis (2-mercaptoethyl)-N′,N′-diethylethylenediamine (BMEDA)-labeled pegylated liposomes have been studied in normal rats [23], the therapeutic applications of nanotargeted 188Re-BMEDA-labeled pegylated liposomes (RBLPL) in malignant ascites and tumor-bearing mice were not reported yet. In this study, biodistribution, pharmacokinetics and micro-single photon emission computed tomography (SPECT)/computed tomography (CT) imaging of ip injection of RBLPL and unencapsulated 188Re-BMEDA were investigated in a C26 colon carcinoma ascites mouse model. The experimental goals are to demonstrate the potential applications of nanotargeted RBLPL via ip route for dual imaging and radiotherapy of peritoneal carcinomatosis and ascites.
Section snippets
Materials
Distearoylphosphatidylcholine (DSPC), cholesterol and polyethylene glycol (average molecular weight, 2000)-derived distearoylphosphatidylethanolamine (PEG-DSPE) were purchased from Genzyme (Cambridge, MA, USA). Cell culture materials were obtained from GIBCO BRL (Grand Island, NY, USA). PD-10 column and Sepharose 4 Fast Flow were purchased from GE Healthcare (Uppsala, Sweden). BMEDA was purchased from ABX (Radeberg, Germany). All other chemicals were purchased from Merck.
Cell line and animal tumor and ascites model
C26 murine colon
Labeling efficiency and radiochemical purity of RBLPL
The labeling efficiency of the 188Re-BMEDA was greater than 95%. The loaded efficiency of RBLPL was 82.3±4.5% (n=3). The radiochemical purity of RBLPL was more than 95%. After 188Re-BMEDA encapsulating into nanopegylated liposomes, the average particle size of RBLPL was 85.1±16.6 nm. They were similar to the particle sizes before 188Re-BMEDA encapsulation.
In vitro stability studies
The in vitro stability of RBLPL after incubation in normal saline at room temperature or rat plasma at 37°C is shown in Table 1. The
Discussion
Radioisotopes can be trapped within the inner space of the liposome [29], intercalated into the double membrane of the liposome or connected with the surface of the liposome for achieving liposome labeling. Reports for the labeling of liposomes with β-emitting therapeutic radionuclides, such as 131I, 90Y, 186Re and 177Lu, have been published [29], [30], [31]. Hafeli et al.[29] reported the 186Re/188Re labeled liposomes, as described previously. The labeling method was impractical for clinical
Conclusion
Our experimental results revealed that the passive nanotargeted radiopharmaceuticals of RBLPL were stable in rat plasma and prolonged retention within the abdominal organs, ascites and tumor nodules of C26 ascites animal model. The biodistribution, pharmacokinetics and the imaging studies of RBLPL on the C26 colon carcinoma tumor ascites model demonstrate good tumor and ascites targeting, bioavailability and localization of nanotargeted RBLPL. The ip administration of the passive nanotargeted
Acknowledgments
The authors thank Mr. C. J. Liu for providing us with the 188Re; Dr. M. L. Jan, Ms. Y. H. Wu and Ms. W. C. Lee for their technical support and Ms. C. C. Chen (National Health Research Institutes, Miaoli,Taiwan, ROC) for assistance in animal tumor and ascites model.
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