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

Program in Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
Journal of Nuclear Medicine (Impact Factor: 6.16). 03/2011; 52(4):625-33. DOI: 10.2967/jnumed.110.083998
Source: PubMed


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.
These preliminary studies use (89)Zr-labeled mouse serum albumin ((89)Zr-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 (89)Zr-desferrioxamine-mAlb.
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.
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.

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    • "Driven by a better understanding of the differences between cancer cells and regular cells, passive and active targeted therapies are being developed to ameliorate the devastating side effects that usually accompany cancer treatment[1]. First, high molecular weight drugs can passively accumulate in tumors by the so-called enhanced permeability and retention (EPR) effect, which is based on the defective vasculature surrounding tumors[2]. Second, covalent modifications (e.g., PEGylation, glycosylation) have increased drug biocompatibility, blood circulation time, and stability[1]Hyaluronic acid (HA) is an attractive candidate for the development of such a DDS because it can be used to construct the bulk matrix, can serve as an active targeting ligand, and could potentially improve drug stability when employing protein drugs like Cyt c used in this work. It is worthwhile to mention that many of the more recent drugs used in cancer treatment are protein drugs, mostly antibodies[3]. "

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    • "Accordingly, free 89 Zr could show nonspecific tumor accumulation through this pathway, which might disturb the correct interpretation of accumulation data from mAb imaging. In addition, enhanced permeation and retention (EPR) dominated localization after metal association with endogenous serum proteins, such as albumin, may give rise to lesion uptake of free 89 Zr [13] [14]. As nanoparticles are typically thought to localize to tumors via EPR [15], the presence of free 89 Zr may have consequences for the interpretation of tumor accumulation data for "
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    ABSTRACT: Preclinical studies involving 89Zr often report significant bone accumulation, which is associated with dissociation of the radiometal from the tracer. However, experiments determining the uptake of unbound 89Zr in disease models are not performed as routine controls. The purpose of the present study was to investigate the impact of free or weakly bound 89Zr on PET quantifications in disease models, in order to determine if such control experiments are warranted.Methods Chemical studies were carried out to find a 89Zr compound that would solubilize the 89Zr as a weak chelate, thus mimicking free or weakly bound 89Zr released in circulation. 89Zr oxalate had the desired characteristics, and was injected into mice bearing FaDu and HT29 solid tumor xenografts, and mice infected in the lungs with the mold Aspergillus fumigatus, as well as in healthy controls (naïve). PET/CT and PET/MR imaging followed to quantify the distribution of the radionuclide in the disease models.Results89Zr oxalate was found to have a plasma half-life of 5.1 ± 2.3 h, accumulating mainly in the bones of all animals. Both tumor types accumulated 89Zr on the order of 2-4% ID/cm3, which is comparable to EPR-mediated accumulation of certain species. In the aspergillosis model, the concentration of 89Zr in lung tissue of the naïve animals was 6.0 ± 1.1 %ID/g. This was significantly different from that of the animals with advanced disease, showing 11.6% ± 1.8 %ID/g.Conclusions Given the high levels of 89Zr accumulation in the disease sites in the present study, we recommend control experiments mapping the biodistribution of free 89Zr in any preclinical study employing 89Zr where bone uptake is observed. Aqueous 89Zr oxalate appears to be a suitable compound for such studies. This is especially relevant in studies where the tracer accumulation is based upon passive targeting, such as EPR.
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    • "Interestingly, in these studies of small metastases, all tracers, including albumin, cleared from the lesions (and brain) by 24 h after administration. This is significantly different than observed for 64 Cu-BSA in larger malignant tumors where much of the BSA tracer remains present for more than 48 h [47] [55] [56]. However, the rapid clearance of gadolinium-based contrast agents we observed in all normal organs including the liver, corresponds to results reported by others [52] [53] [57] [58]. "
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    ABSTRACT: Our goal was to develop strategies to quantify the accumulation of model therapeutics in small brain metastases using multimodal imaging, in order to enhance the potential for successful treatment. Human melanoma cells were injected into the left cardiac ventricle of immunodeficient mice. Bioluminescent, MR and PET imaging were applied to evaluate the limits of detection and potential for contrast agent extravasation in small brain metastases. A pharmacokinetic model was applied to estimate vascular permeability. Bioluminescent imaging after injecting D-Luciferin (molecular weight (MW) 320D) suggested tumor cell extravasation had already occurred at week 1, which was confirmed by histology. 7T T1w MRI at week 4 was able to detect non-leaky 100 μm sized lesions and leaky tumors with diameters down to 200μm after contrast injection at week 5. PET imaging showed that (18)F-FLT (MW 244D) accumulated in the brain at week 4. Gadolinium-based MRI tracers (MW 559D and 2.066kD) extravasated after 5weeks (tumor diameter 600 μm), and the lower MW agent cleared more rapidly from the tumor (mean apparent permeabilities 2.27x10(-5)cm/s versus 1.12x10(-5)cm/s). PET imaging further demonstrated tumor permeability to (64)Cu-BSA (MW 65.55kD) at week 6 (tumor diameter 700 μm). In conclusion, high field T1w MRI without contrast may improve the detection limit of small brain metastases, allowing for earlier diagnosis of patients, although the smallest lesions detected with T1w MRI were permeable only to D-Luciferin and the amphipathic small molecule (18)F-FLT. Different-sized MR and PET contrast agents demonstrated the gradual increase in leakiness of the blood tumor barrier during metastatic progression, which could guide clinicians in choosing tailored treatment strategies.
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