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.
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.
- [Show abstract] [Hide abstract]
ABSTRACT: The main aim of this work was to evaluate a nanoconjugate system of paclitaxel loaded self-assembling, biodegradable micelles for targeting CD44 overexpression in cancer cells. The shape and size, zeta potential, encapsulation efficiency and cell uptake of these drug-loaded micelles were evaluated. To understand their bio distribution profile, the hyaluronate (HA) micelles were labeled with Flamma™-774 NIR dye and injected into SCC7 tumor induced mice. Cell viability in response to drug loaded and unloaded micelles was studied in SCC7 cancer cells using the MTS assay. An in vivo tumor inhibition study was conducted by intravenous injection of paclitaxel-loaded HA micelle nanoparticles as well as control nanoparticles without paclitaxel. The shape of the nanomicelles was evaluated by loading them with hydrophobic superparamagnetic iron oxide nanoparticle and then visualizing them by TEM. In conclusion, paclitaxel-loaded HA nanoparticulate micelles might be found to be a specific and efficient chemotherapeutic treatment for CD44 overexpressing cancer cells.International Journal of Biological Macromolecules 09/2014; 72. · 3.10 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Histidine-rich glycoprotein (HRG) is implicated in tumor growth and metastasis by regulation of angiogenesis and inflammation. HRG is produced by hepatocytes and carried to tissues via the circulation. We hypothesized that HRG's tissue distribution and turnover may be mediated by inflammatory cells. Biodistribution parameters were analyzed by injection of radiolabeled, bioactive HRG in the circulation of healthy and tumor-bearing mice. 125I-HRG was cleared rapidly from the blood and taken up in tissues of healthy and tumor-bearing mice, followed by degradation, to an increased extent in the tumor-bearing mice. Steady state levels of HRG in the circulation were unaffected by the tumor disease both in murine tumor models and in colorectal cancer (CRC) patients. Importantly, stromal pools of HRG, detected in human CRC microarrays, were associated with inflammatory cells. In agreement, microautoradiography identified 125I-HRG in blood vessels and on CD45-positive leukocytes in mouse tissues. Moreover, radiolabeled HRG bound in a specific, heparan sulfate-independent manner, to differentiated human monocytic U937 cells in vitro. Suppression of monocyte differentiation by systemic treatment of mice with anti-colony stimulating factor-1 neutralizing antibodies led to reduced blood clearance of radiolabeled HRG and to accumulation of endogenous HRG in the blood. Combined, our data show that mononuclear phagocytes have specific binding sites for HRG and that these cells are essential for uptake of HRG from blood and distribution of HRG in tissues. Thereby, we confirm and extend our previous report that inflammatory cells mediate the effect of HRG on tumor growth and metastatic spread.PLoS ONE 09/2014; 9(9):e107483. · 3.53 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Objective: A new transplantable ovarian tumor model is presented using a novel folate receptor (FR) positive, murine ovarian cancer cell line that emulates the human disease and induces widespread intraperitoneal (i.p.) tumors in immunocompetent mice within 4-8 weeks of implantation. Tumor development was monitored using a new PET FR-targeting reporter with PET/CT and fluorescence molecular tomography (FMT) using a commercial FR-targeting reporter. Conventional structural MRI was also performed. Methods: Adult female C57BL/6 mice were injected i.p. with 6 x 106 MKP-L FR+ cells. Imaging was performed weekly beginning 2 weeks after tumor induction. The albumin-binding, FR-targeting ligand cm09 was radiolabeled with the positron emitter 68Ga and used to image the tumors with a small animal PET/CT. The FR-reporter FolateRSense 680 (Perkin Elmer) was used for FMT and flow cytometry. Preclinical MRI (7 T) without FR-targeting was compared with the PET and FMT molecular imaging. Results: Tumors were visible by all 3 imaging modalities. PET/CT had the highest imaging sensitivity at 3-3.5 h post administration (mean %IA/g mean > 6), and visualized tumors earlier than the other two modalities with lower kidney uptake (mean %IA/g mean < 17) than previously reported FR targeting agents in late stage disease. FMT showed relatively low FR-targeted agent in the bladder and kidneys, but yielded the lowest anatomical image resolution. MRI produced the highest resolution images, but it was difficult to distinguish tumors from abdominal organs during early progression since a FR-targeting MRI reporter was not used. Nevertheless, there was good correlation of imaging biomarkers between the three modalities. Conclusions: Tumors in the mouse ovarian cancer model could be detected using FR-targeted imaging as early as two weeks post i.p. injection of tumor cells. An imaging protocol should combine one or more of the modalities, e.g., PET/CT or PET/MRI for optimal tumor detection and delineation from surrounding tissues.Molecular Pharmaceutics 12/2014; · 4.79 Impact Factor