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Characterization of organ-specific immunoliposomes for delivery of 3′,5′-O-dipalmitoyl-5-fluoro-2′-deoxyuridine in a mouse lung-metastasis model

  • Original Article
  • Immunoliposome, Lipophilic Prodrug, Lung Targeting
  • Published:
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Abstract

A previous study has shown that lipophilic prodrugs can be delivered efficiently to normal lung endothelium by incorporation into liposomes covalently conjugated to monoclonal antibody (mAb) 34A against the lung endothelial anticoagulant protein thrombomodulin. In the present study, the potential use of these lung-targeted immunoliposomes (34A-liposomes) for delivery of a lipophilic prodrug, 3′,5′-O-dipalmitoyl-5-fluoro-2′-deoxyuridine (dpFUdR), to the tumor-bearing lung was examined using BALB/c mice bearing experimental lung metastasis induced by i.v. injection of EMT-6 mouse mammary tumor cells. Immunohistochemical examination of the tumor-bearing lung showed specificity of mAb 34A to lung endothelium. Tumor cells appeared to localize just outside of the normal blood vessels and were within a small diffusion distance from the mAb 34A-binding sites.111In-labeled 34A-liposomes containing monosialoganglioside (GM1) were prepared that included [3H]-dpFUdR at 3.0 mol% in the lipid mixture. In vitro cell binding studies further demonstrated that 34A-liposomes bound specifically to normal mouse lung cells that expressed thrombomodulin but not to EMT-6 cells. Biodistribution study showed efficient and immunospecific accumulation of [3H]-dpFUdR incorporated into 34A-liposomes in the lung at a level parallel with that of111In-labeled 34A-liposomes, indicating that the drug is delivered to the target organ in intact liposomes. Liposomal dpFUdR appeared to be metabolized in the lung to the parent drug FUdR at a rate slower than in the liver and spleen. Furthermore, treatment of lung-metastasis-bearing mice with dpFUdR incorporated into 34A-liposomes on days 1 and 3 after tumor cell injection resulted in a significant increase in the median survival time of treated mice as compared with control mice (%T/C value, 165%). dpFUdR either dispersed in emulsion or incorporated into antibody-free liposomes was ineffective in prolonging the survival of mice. These results indicate the potential effectiveness of organ-specific immunoliposomes containing a lipophilic prodrug for the targeted therapy of metastatic tumors.

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Abbreviations

Chol :

Cholesterol

dpFUdR :

3′,5′-O-dipalmitoyl-5-fluoro-2′-deoxyuridine

DTPA-SA :

diethylenetriamine pentaacetic acid distearylamide complex

G M 1 :

monosialoganglioside

IC 50 :

50% inhibitory concentration

mAb :

monoclonal antibody

MST :

mean survival time

NGPE :

N-glutaryl phosphatidylethanolamine

NMLC :

normal mouse lung cells

OG :

octyl-β-d-glucopyranoside

PBS :

phosphate-buffered saline

PC :

egg phosphatidylcholine

%T/C :

(median survival time of treated mice divided by the median survival time of control mice) x100

RES :

reticuloendothelial system

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Authors and Affiliations

  1. Department of Pharmacology, University of Pittsburgh School of Medicine, 13th Floor, Biomedical Science Tower, 15261, Pittsburgh, PA, USA

    Atsuhide Mori & Leaf Huang

  2. Biology Division, Oak Ridge National Laboratory, 37830, Oak Ridge, TN, USA

    Stephen J. Kennel

  3. Groningen Institute for Drug Studies, Laboratory of Physiological Chemistry, Groningen University, Groningen, The Netherlands

    Marjan van Borssum Waalkes & Gerrit L. Scherphof

Authors
  1. Atsuhide Mori
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  2. Stephen J. Kennel
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  3. Marjan van Borssum Waalkes
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  4. Gerrit L. Scherphof
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  5. Leaf Huang
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This manuscript was authored by a contractor of the United States Government under contract DE-AC05-84OR21400. Accordingly, the United States Government retains a nonexclusive, royalty-free licence to publish or reproduce the published form of this contribution, or to allow others to do so, for United States Government purposes.

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Mori, A., Kennel, S.J., van Borssum Waalkes, M. et al. Characterization of organ-specific immunoliposomes for delivery of 3′,5′-O-dipalmitoyl-5-fluoro-2′-deoxyuridine in a mouse lung-metastasis model. Cancer Chemother. Pharmacol. 35, 447–456 (1995). https://doi.org/10.1007/BF00686828

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  • DOI: https://doi.org/10.1007/BF00686828

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