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

Abstract

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.

Immuno-PET Imaging of CD30-Positive Lymphoma Using 89Zr-Desferrioxamine–Labeled CD30-Specific AC-10 Antibody

“…5 and 6B). 89 Zr-DFO-AC-10 uptake in the CD30-negative model is attributed to passive accumulation via the established mechanism of enhanced permeability and retention, and our data are consistent with other reports of 89 Zr-DFO-mAb radiotracers in equivalent antigen-negative tumor models (21,23,24).…”

Ultrasound drug targeting to tumors with thermosensitive liposomes

“…In a second series of testing, orthotopic EMT-6 tumors were heated: in this model, elevation of temperature to 41-43 o C was not as instantaneous (1-2 minutes), and throughout the course of heating (20 min), the output of the frequency generator had to be increased to maintain even heating. This particular observation was expected, as orthotopic tumors tend to be more heavily vascularized [21][22][23], perfusion is known to influence heat transfer, and vascular parameters in turn are influenced by heating [13,24]. In the footpad model, post HaT-DOX therapy, treated mice exhibited swollen feet and redness in the tumor, a response to treatment consistent with doxorubicin therapy seen in other models.…”

ABT-414, an Antibody–Drug Conjugate Targeting a Tumor-Selective EGFR Epitope

“…This growth inhibition by IgG-mcMMAF is likely a result of the enhanced permeability and retention effect resulting from antibody or ADC accumulation in tumors rather than the recognition of a tumor-associated antigen (27)(28)(29).…”