Biodistribution, pharmacokinetics and imaging of 188Re-BMEDA-labeled pegylated liposomes after intraperitoneal injection in a C26 colon carcinoma ascites mouse model

https://doi.org/10.1016/j.nucmedbio.2007.02.003Get rights and content

Abstract

Nanoliposomes are important carriers capable of packaging drugs for various delivery applications through passive targeting tumor sites by enhanced permeability and retention effect. Radiolabeled liposomes have potential applications in radiotherapy and diagnostic imaging. The purpose of this study was to investigate the biodistribution, pharmacokinetics and imaging of nanotargeted 188Re-N,N-bis (2-mercaptoethyl)-N′,N′-diethylethylenediamine (BMEDA)-labeled pegylated liposomes (RBLPL) and unencapsulated 188Re-BMEDA after intraperitoneal (ip) injection in a C26 colon carcinoma ascites mouse model. The nanopegylated liposomes were labeled with 188Re-BMEDA. The labeling efficiency of RBLPL was 82.3±4.5%. In vitro stability of RBLPL in normal saline at room temperature and in rat plasma at 37°C for 72 h was 92.01±1.31% and 82.4±1.64%, respectively. The biodistribution studies indicated that the radioactivity in ascites was 69.96±14.08 percentage injected dose per gram (% ID/g) at 1h to 5.99±1.97% ID/g at 48 h after ip administration of RBLPL. The levels of radioactivity in tumor were progressive accumulation to a maximum of 6.57±1.7% ID/g at 24 h. The radioactivity of 188Re-BMEDA in ascites reached the maximum level of 54.89±5.91% ID/g at 1 h and declined rapidly with time. Pharmacokinetic studies revealed that the terminal half-life, total body clearance and area under the curve of RBLPL were 5.3-, 9.5- and 9.4-fold higher than that of 188Re-BMEDA in blood, respectively. These results suggested that the long circulation, bioavailability and localization of RBLPL in tumor and ascites sites, which also demonstrate that the ip administration of RBLPL is a potential multifunctional nanoradiotherapeutics and imaging agents on 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.

References (40)

  • S.K. Huang et al.

    Extravasation and transcytosis of liposomes in Kaposi's sarcoma-like dermal lesions of transgenic mice bearing the HIV tat gene

    Am J Pathol

    (1993)
  • M.S. Newman et al.

    Comparative pharmacokinetics, tissue distribution, and therapeutic effectiveness of cisplatin encapsulated in long-circulating, pegylated liposomes (SPI-077) in tumor-bearing mice

    Cancer Chemother Pharmacol

    (1999)
  • J. Vaage et al.

    Therapy of a xenografted human colonic carcinoma using cisplatin or doxorubicin encapsulated in long-circulating pegylated stealth liposomes

    Int J Cancer

    (1999)
  • A. Gabizon et al.

    Pharmacokinetics of pegylated liposomal Doxorubicin: review of animal and human studies

    Clin Pharmacokinet

    (2003)
  • B. Eisenberg et al.

    Carcinoma of the colon and rectum: the natural history reviewed in 1704 patients

    Cancer

    (1982)
  • R. Sood

    Ascites: diagnosis and management

    JIACM

    (2000)
  • M. Markman

    Intraperitoneal chemotherapy in the management of colon cancer

    Semin Oncol

    (1999)
  • S.R. Pestieau et al.

    Treatment of primary colon cancer with peritoneal carcinomatosis: comparison of concomitant vs. delayed management

    Dis Colon Rectum

    (2000)
  • K.N. Syrigos et al.

    Biodistribution and pharmacokinetics of 111In-dTPA-labelled pegylated liposomes after intraperitoneal injection

    Acta Oncol

    (2003)
  • J.L. Speyer

    The rationale behind intraperitoneal chemotherapy in gastrointestinal malignancies

    Semin Oncol

    (1985)
  • Cited by (70)

    • Nanovesicles for image-guided drug delivery

      2022, Systems of Nanovesicular Drug Delivery
    • Nuclear imaging approaches facilitating nanomedicine translation

      2020, Advanced Drug Delivery Reviews
      Citation Excerpt :

      Conveniently, the radiation of radiotherapeutic isotopes is typically accompanied by emission of gamma photons that can be detected by SPECT. For example, Ting et al. have exploited this feature using 188Re-labeled liposomes for radiotherapy and detecting the concomitant 155-keV gamma photons to assess biodistribution and absorbed dose by SPECT [123–125]. Conversely, liposomes loaded with the β-emitter 177Lu were used in a human xenograft mouse model and the authors used surrogate 64Cu-loaded liposomes to extract in vivo information by PET imaging, including dosimetric data and tumor absorbed dose [176].

    • Liposomes and micelles as nanocarriers for diagnostic and imaging purposes

      2018, Design of Nanostructures for Theranostics Applications
    • The PEGylated liposomal doxorubicin improves the delivery and therapeutic efficiency of <sup>188</sup>Re-Liposome by modulating phagocytosis in C26 murine colon carcinoma tumor model

      2014, Nuclear Medicine and Biology
      Citation Excerpt :

      C26 cells were detached with 0.05% trypsin/0.53 mM EDTA in Hanks' Balanced Salt Solution. The preparation for 188Re-Liposomes was performed as described [27,29]. Principally, it is BMEDA (ABX) used as a chelator and stannous chloride (MERCK) was used as the reductant and glucoheptonate (Sigma-Aldrich) was used as an intermediate ligand to make 188Re-SNS/S complexes.

    View all citing articles on Scopus
    View full text