Magnitude of Enhanced Permeability and Retention Effect in Tumors with Different Phenotypes: 89Zr-Albumin as a Model System

Targeted nanoparticle-based technologies show increasing prevalence in radiotracer design. As a consequence, quantitative contribution of nonspecific accumulation in the target tissue, mainly governed by the enhanced permeability and retention (EPR) effect, becomes highly relevant for evaluating the specificity of these new agents. This study investigated the influence of different tumor phenotypes on the EPR effect, hypothesizing that a baseline level of uptake must be exceeded to visualize high and specific uptake of a targeted macromolecular radiotracer. Methods: These preliminary studies use 89Zr-labeled mouse serum albumin (89Zr-desferrioxamine-mAlb) as a model radiotracer to assess uptake and retention in 3 xenograft models of human prostate cancer (CWR22rv1, DU-145, and PC-3). Experiments include PET and contrast-enhanced ultrasound imaging to assess morphology, vascularization, and radiotracer uptake; temporal ex vivo biodistribution studies to quantify radiotracer uptake over time; and histologic and autoradiographic studies to evaluate the intra- and intertumoral distribution of 89Zr-desferrioxamine-mAlb. Results: Early uptake profiles show statistically significant but overall small differences in radiotracer uptake between different tumor phenotypes. By 20 h, nonspecific radiotracer uptake was found to be independent of tumor size and phenotype, reaching at least 5.0 percentage injected dose per gram in all 3 tumor models. Conclusion: These studies suggest that minimal differences in tumor uptake exist at early time points, dependent on the tumor type. However, these differences equalize over time, reaching around 5.0 percentage injected dose per gram at 20 h after injection. These data provide strong support for the introduction of mandatory experimental controls of future macromolecular or nanoparticle-based drugs, particularly regarding the development of targeted radiotracers.

[1]  Vladimir Torchilin,et al.  Tumor delivery of macromolecular drugs based on the EPR effect. , 2011, Advanced drug delivery reviews.

[2]  S. Larson,et al.  89Zr-DFO-J591 for ImmunoPET of Prostate-Specific Membrane Antigen Expression In Vivo , 2010, The Journal of Nuclear Medicine.

[3]  J. Holland,et al.  89Zr-chemistry in the design of novel radiotracers for immunoPET , 2010 .

[4]  Eva Frei,et al.  Native albumin for targeted drug delivery , 2010, Expert opinion on drug delivery.

[5]  Hiroshi Maeda,et al.  Tumor-selective delivery of macromolecular drugs via the EPR effect: background and future prospects. , 2010, Bioconjugate chemistry.

[6]  Valerie A Longo,et al.  Measuring the Pharmacodynamic Effects of a Novel Hsp90 Inhibitor on HER2/neu Expression in Mice Using 89Zr-DFO-Trastuzumab , 2010, PloS one.

[7]  Ruth Duncan,et al.  Development of HPMA copolymer-anticancer conjugates: clinical experience and lessons learnt. , 2009, Advanced drug delivery reviews.

[8]  Jason S. Lewis,et al.  Standardized methods for the production of high specific-activity zirconium-89. , 2009, Nuclear medicine and biology.

[9]  S. Yeh,et al.  Tissue prostate-specific antigen facilitates refractory prostate tumor progression via enhancing ARA70-regulated androgen receptor transactivation. , 2008, Cancer research.

[10]  W. Hahn,et al.  The current state of preclinical prostate cancer animal models , 2008, The Prostate.

[11]  R. Kiwan,et al.  Antitumor activity of new liposomal prodrug of mitomycin C in multidrug resistant solid tumor: Insights of the mechanism of action , 2007, Journal of drug targeting.

[12]  M. Radmacher,et al.  Albumin turnover: FcRn-mediated recycling saves as much albumin from degradation as the liver produces. , 2006, American journal of physiology. Gastrointestinal and liver physiology.

[13]  M. Suetsugi,et al.  Expression and functional study of estrogen receptor-related receptors in human prostatic cells and tissues. , 2005, The Journal of clinical endocrinology and metabolism.

[14]  J. Brown,et al.  Exploiting tumour hypoxia in cancer treatment , 2004, Nature Reviews Cancer.

[15]  R. Boellaard,et al.  89Zr immuno-PET: comprehensive procedures for the production of 89Zr-labeled monoclonal antibodies. , 2003, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[16]  H. Maeda,et al.  Mechanism of tumor-targeted delivery of macromolecular drugs, including the EPR effect in solid tumor and clinical overview of the prototype polymeric drug SMANCS. , 2001, Journal of controlled release : official journal of the Controlled Release Society.

[17]  H. Fiebig,et al.  Pre‐clinical evaluation of a methotrexate–albumin conjugate (MTX‐HSA) in human tumor xenografts in vivo , 2001, International journal of cancer.

[18]  Janice M. Y. Brown,et al.  The hypoxic cell: a target for selective cancer therapy--eighteenth Bruce F. Cain Memorial Award lecture. , 1999, Cancer research.

[19]  A. Giaccia,et al.  The unique physiology of solid tumors: opportunities (and problems) for cancer therapy. , 1998, Cancer research.

[20]  A R Jayaweera,et al.  Quantification of myocardial blood flow with ultrasound-induced destruction of microbubbles administered as a constant venous infusion. , 1998, Circulation.

[21]  A. Wunder,et al.  Plasma protein (albumin) catabolism by the tumor itself--implications for tumor metabolism and the genesis of cachexia. , 1997, Critical reviews in oncology/hematology.

[22]  P. Cutler,et al.  Preparation, biodistribution and dosimetry of copper-64-labeled anti-colorectal carcinoma monoclonal antibody fragments 1A3-F(ab')2. , 1995, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[23]  T. Okano,et al.  Improved synthesis of adriamycin-conjugated poly (ethylene oxide)-poly (aspartic acid) block copolymer and formation of unimodal micellar structure with controlled amount of physically entrapped adriamycin , 1994 .

[24]  H. Maeda,et al.  Conjugates of anticancer agents and polymers: advantages of macromolecular therapeutics in vivo. , 1992, Bioconjugate chemistry.

[25]  H. Maeda,et al.  SMANCS and polymer-conjugated macromolecular drugs: advantages in cancer chemotherapy. , 1991, Advanced drug delivery reviews.

[26]  H. Maeda,et al.  A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. , 1986, Cancer research.

[27]  J. Levick Permeability of rheumatoid and normal human synovium to specific plasma proteins. , 1981, Arthritis and rheumatism.

[28]  M. Mimeault,et al.  Recent advances on multiple tumorigenic cascades involved in prostatic cancer progression and targeting therapies. , 2006, Carcinogenesis.