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Experimental Studies |
1 From the Department of Radiology, Center for Molecular Imaging Research, Massachusetts General Hospital, Bldg 149, 13th St, 5403, Charlestown, MA 02129. Received February 1, 1999; revision requested March 15; revision received March 26; accepted June 28. Supported in part by National Institutes of Health grant nos. 5-RO1-NS335258-03, 5-RO1-CA54886-06, RO1-CA7442401 and 2-RO1-CA5964905. E.M. supported by a Fellowship Award from the Center for Innovative Minimally Invasive Therapy (CIMIT) at Massachusetts General Hospital. Address reprint requests to R.W. (e-mail: weissleder@helix.mgh.harvard.edu).
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Abstract |
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MATERIALS AND METHODS: A gliosarcoma rodent model was established to determine the distribution of a model LCDIO preparation in tumors. LCDIO accumulation in tissue sections was evaluated with multichannel fluorescence microscopy with rhodaminated LCDIO, green fluorescent protein as a tumor marker, and Hoechst 33258 dye as an intravital endothelial stain. Uptake into tumor cells was corroborated with results of immunohistochemical and cell culture uptake experiments. The effect of intratumoral LCDIO uptake on magnetic resonance (MR) imaging signal intensity was evaluated with a 1.5-T superconducting magnet.
RESULTS: Tumoral accumulation of LCDIO was 0.11% ± 0.06 of the injected dose per gram of tissue in brain tumors and was sufficient for detection at MR imaging. In tumor sections, LCDIO was preferentially localized in tumor cells (49.0% ± 4.6) but was also taken up by macrophages in tumors (21.0% ± 3.1) and by endothelial cells in the areas of active angiogenesis (6.5% ± 1.4). In cell culture, LCDIO uptake was strongly correlated with growth rate of tumor cell lines.
CONCLUSION: Tumoral LCDIO accumulation was not negligible and helped explain MR imaging signal intensity changes observed in clinical trials. Microscopically, LCDIO accumulated predominantly in tumor cells and tumor-associated macrophages. Uptake into tumor cells appeared to be directly proportional to cellular proliferation rates.
Index terms: Animals • Brain, iron • Brain neoplasms, 10.363 • Brain neoplasms, MR, 10.121412, 10.12146 • Contrast media, experimental studies • Iron • Neoplasms, experimental studies, 10.363
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Introduction |
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The old paradigm that iron oxides accumulate in the reticuloendothelial system but not in tumors has recently been challenged. Indeed it has been observed that LCDIO nanoparticles penetrate through the capillary endothelium of the tumor (10,11) and are internalized in tumor cells (10,12). These observations have also been supported by the results of cell culture studies (13), which confirmed that endocytosis of LCDIO nanoparticles occurs in tumor cells. Furthermore, results from clinical trials (14) have confirmed that primary malignancies show particular signal intensity changes after intravenous administration of LCDIO nanoparticles.
The goal of the current study was to determine the magnitude and pattern of tumoral LCDIO uptake, with attention to their relevance for the interpretation of MR images. Because conventional histologic staining techniques are not very sensitive or specific for iron, we used alternative approaches, including the use of genetically engineered tumor cells that expressed the green-fluorescent-protein (GFP) marker, the use of antidextran antibodies, and compartmental analysis with radiolabeled LCDIO nanoparticles to directly quantify accumulation and distribution of the probe in vivo. The results of the current investigation may provide a better understanding of the interaction of LCDIO particles with different cell populations in tumors and may assist in interpretation of clinically obtained MR images.
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MATERIALS AND METHODS |
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TOPAbstractIntroductionMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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The LCDIO was labeled with iodine 125 to enable quantification of iron uptake by the cells. Iodination of LCDIO was performed with sodium iodide I 125 (574 mCi [2.1 x 104 MBq] per millimole of iron; 0.1 mol/L sodium carbonate, pH 9.0) in the presence of an iodination reagent (IodoGen; Pierce Chemical, Rockford, Ill). The compound was purified after iodination by means of gel filtration through a Sephadex G-25m column (Sigma Chemical) saturated with bovine serum albumin. The LCDIO nanoparticles also were labeled with a fluorescent label (rhodamine) for microscopy, as has been described elsewhere (15).
Cell Lines
The following cell lines and primary isolates of different origin and differentiation were used for cellular uptake experiments: SVEC 4–10 endothelial cells (mouse), 9L gliosarcoma cells (rat), C6 glioma cells (rat), J774 macrophage-like sarcoma cells (rat), U87 gliosarcoma cells (human), LX1 small cell lung carcinoma cells (human), HBL100 mammary adenocarcinoma cells (human), D4.475 mammary adenocarcinoma cells (human), MCF-7 mammary adenocarcinoma cells (human), LS174T colon adenocarcinoma cells (human), mouse peritoneal macrophages, mouse and rat lymph nodal lymphocytes, mouse and rat splenic lymphocytes, and human peripheral blood lymphocytes (Table 1).
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Cellular Uptake Experiments
To determine the amount of LCDIO internalized in cells, we used a quantitative cellular uptake assay. Cell suspensions (100,000 cells each of LX1, D4.475, and primary isolate lines) were placed into plastic tubes that contained 1 mL of the corresponding medium with different concentrations (1, 5, 25, 50, 75, and 100 µg) of 125I-labeled LCDIO. Cells were incubated at 37°C for 1 hour and were then washed three times by means of centrifugation through a step gradient of 40% Histopaque-1077 (Sigma Chemical) in Hanks balanced salt solution.
After the last centrifugation and aspiration of the supernatant fluid, cell pellets were counted in a gamma counter (1289 Compugamma LS; Wallac, Turku, Finland). Anchorage-dependent cells (SVEC4-10, 9L, C6, J774, U87, HBL100, MCF-7, and LS174T cell lines) were plated (100,000 cells) on 12-well plates in 1 mL of culture medium each. 125I-labeled LCDIO was added at the same concentrations as described in the previous paragraph. Cells were incubated for 1 hour, washed three times with Hanks balanced salt solution, lysed in 0.5 mL 1% Triton X-100, and counted in a gamma counter. All cellular uptake experiments were performed in duplicate, and the results were normalized for total cellular protein content (BCA protein assay; Pierce Chemical). Determination of cell doubling time was performed as described elsewhere (16).
Transfection and Selection of GFP-expressing Tumor Cell Line
To determine the spatial distribution in the tumor of the fluorescently labeled LCDIO nanoparticles, we developed a 9L gliosarcoma cell line that had been stably transfected with a mammalian expression vector (pcDNA3; Invitrogen, Carlsbad, Calif) encoding enhanced humanized GFP (phGFP-S65T; Seed B, Boston, Mass) (17,18). The original GFP complementary DNA fragment (716 base pairs) was recloned into the HindIII and NotI restriction sites of the pcDNA3 vector. Restriction analysis and partial sequencing results confirmed the integrity of the GFP complementary DNA fragment.
The 9L cells were transfected by using the TransIT-100 transfection reagent (PanVera; Madison, Wis). Cells were plated on a 10-cm-diameter Petri dish in Dulbecco modified Eagle medium with 10% fetal bovine serum (1.2 x 106 cells per dish) 24 hours before transfection. The transfection reagent (32.4 µL) was added dropwise to 810 µL of Dulbecco modified Eagle medium without fetal bovine serum and incubated for 5 minutes. Plasmid (17 µg) was added to the mixture and incubated for another 5 minutes. Complete medium was removed, and cells were washed with serum-free Dulbecco modified Eagle medium. Serum-free Dulbecco modified Eagle medium was then added to the cells, and the transfection reagent–DNA complex mixture was applied and evenly distributed on the dish. After 5 hours of incubation, the medium was removed and replaced with complete growth medium. Seventy-two hours later, the cells were subcultured at a 1:6 ratio in selection medium (Dulbecco modified Eagle medium with 10% fetal bovine serum and 1 mg/mL antibiotic G418 [Geneticin Disulfate Salt; Sigma Chemical]).
After 3 weeks of selection and visual observation of clones by using an inverted fluorescence microscope (Axiovert 100TV; Zeiss, Wetzlar, Germany) equipped with a fluorescein isothiocyanate filter set (Omega Optical, Brattleboro, Vt), positive fluorescent clones were selected by means of cylindric cloning. Stably transfected cells were maintained in culture as described earlier in this article. The stability of the cell line was periodically validated by analyzing the cells with a fluorescence-activated cell sorter.
Tumor Model and MR Imaging
Ten female Fischer 344 rats (Charles River Breeding Laboratories, NC) (weight, 180–200 g) were used for intracerebral implantation of GFP-expressing 9L (ie, 9L-GFP) glioma cells. The animals were anesthetized with an intraperitoneal injection of 80 mg of ketamine hydrochloride per kilogram of body weight (mg/kg) (Parke-Davis, Morris Plains, NJ) and 12 mg/kg xylazine (Miles, Shawnee Mission, Kan) and were immobilized in a stereotactic frame (David Kopf Instruments, Tujunga, Calif). A linear skin incision was performed over the bregma, and a 1-mm-diameter burr hole was drilled into the skull approximately 0.5 mm posterior and 3.5 mm lateral to the bregma. A 10-µL syringe (Hamilton, Reno, Nev) was used to inject 10 µL of the 9L cell suspension (approximately 1 million cells in a phosphate-buffered saline solution) into the putamen at a depth of 3.5 mm from the dural surface. The injection was administered for 5 minutes, and the needle was withdrawn slowly for another 5 minutes. The burr hole was occluded with bone wax (Ethicon, Sommerville, NJ) to prevent leakage of cerebrospinal fluid, and the skin was closed with a suture. The animal protocol was approved by the institutional review committee on animal care and was conducted in accordance with national animal welfare guidelines.
MR imaging was performed 14 days after tumor implantation. All animals were initially imaged before and 24 hours after injection of LCDIO (10 mg/kg iron). Rats were anesthetized for imaging as described earlier in this article and were immobilized on a small piece of fiberglass for more accurate positioning and to prevent motion artifacts. All images were obtained with a 1.5-T superconducting magnet (Signa; GE Medical Systems, Milwaukee, Wis) by using a surface coil with a 3-inch (7.6-cm) diameter. Transverse T1-weighted three-dimensional spoiled gradient-echo MR images were obtained with the following parameters: 60/14 (repetition time msec/echo time msec), 60° flip angle, four signals acquired, 256 x 192 matrix, 10-cm field of view, and 1-mm section thickness. Transverse T2-weighted three-dimensional spoiled gradient-echo images were obtained with the following parameters: 60/30, 10° flip angle, 256 x 192 matrix, four signals acquired, 10-cm field of view, and 1-mm section thickness. The MR images were retrospectively evaluated by one of two investigators (A.M., E.M.), who determined the size, signal intensity characteristics, and effects of LCDIO administration.
The distribution in tissue and accumulation in tumor of LCDIO nanoparticles were assessed at 24 hours after intravenous injection of 10 µCi (0.37 MBq) of 125I-labeled LCDIO (10 mg/kg iron) into another four rats. Tissues and body fluids (tumor, brain, heart, intestine, liver, spleen, kidney, muscle, bone, lung, lymph nodes, and blood) were obtained, blotted dry, weighed, sealed in test tubes, and counted in a gamma counter. The concentration of LCDIO was expressed as the percentage of injected dose per gram of tissue.
Immunohistochemistry
To visualize the dextran coating of LCDIO nanoparticles in tumoral tissue, we investigated several noncommercial antidextran antibodies (10.16.1 immunoglobulin A; courtesy of Denong Wang, MD, PhD, Columbia Genome Center, Columbia University, New York, NY [19]), compared their reactivity against 11-kD 512 B dextran from Leuconostoc mesenteroides by means of enzyme-linked immunosorbent assay, and then optimized their immunohistochemical properties by using the antibody with the highest affinity. Briefly, frozen tissues were cut into 8-µm-thick sections at 100-µm intervals (2800 Frigocut-E; Leica Instruments, Nussloch, Germany). Sections were fixed in 4% formaldehyde, washed with phosphate-buffered saline solution (at pH 7.4), and incubated with an optimizing antidextran antibody for 1 hour. Sections were incubated with biotinylated antimouse immunoglobulin A antibodies and consequently with avidin-peroxidase conjugate (Bio-Rad, Richmond, Calif). The sections were dehydrated and counterstained with Gill #1 hematoxylin (Fisher Scientific, Fair Lawn, NJ). Control staining was performed in the absence of the primary or secondary antibodies. Staining for macrophages was performed according to manufacturer's instructions by using a kit for 
-naphthyl acetate esterase activity (procedure no. 90; Sigma Chemical).
Fluorescence Microscopy
Fluorescence microscopy was used to help differentiate among individual cellular compartments of tumors (tumor cells, macrophages, endothelial cells, and tumoral interstitium) that contained LCDIO. Fluorescence was observed in three channels: green (tumor cells expressing GFP; excitation, 485 nm; emission, 530 nm), red (rhodamine-labeled LCDIO; excitation, 570 nm; emission, 590 nm), and blue (endothelial cells stained with Hoechst dye; excitation, 365 nm; emission, 450 nm).
Tumor-bearing rats received an intravenous injection of rhodamine-labeled LCDIO (10 mg/kg iron) followed 24 hours later by 100 µL of 0.2% Hoechst 33258 dye (Molecular Probes, Eugene, Ore), immediately prior to sacrifice. The brain was removed, frozen in liquid nitrogen, and cut into 8-µm-thick sections. Three-channel images were collected by using a cooled charge-coupled device (Sensys; Photometrics, Tucson, Ariz) with appropriate excitation and emission filters (Omega Optical).
Analysis
Histologic image analysis included immunohistologically stained sections to visualize LCDIO in tumor and fluorescence microscopy sections to determine which tumoral cellular components contained LCDIO. Fluorescence microscopy of individual tumoral components and rhodamine-labeled LCDIO distribution in these components was performed prior to histologic analysis. Next, the same consecutive histologic sections were stained for dextran and macrophages (-naphthyl acetate esterase activity). The distributions of rhodamine-labeled LCDIO in tumor cells and in endothelial cells were evaluated with fluorescence microscopy. The distribution in macrophages was assessed by superimposing sections stained for dextran or macrophages. Interstitial volume was calculated by subtracting the cellular volume fraction (area occupied by macrophages and endothelial and tumor cells) from the total area of the tumor on nonfixed sections. All calculations were performed at x100 magnification of a 1-mm2 examination area by using the cooled charge-coupled device and IPLAB SPECTRUM software (version 3.1; Signal Analytics, Vienna, Va).
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RESULTS |
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TOPAbstractIntroductionMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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-naphthyl acetate esterase activity (21.0% ± 3.1 of tumoral dose), and vascular endothelial cells, as stained with the Hoechst dye (6.5% ± 1.4). Figure 3 shows LCDIO accumulation in tumor cells as revealed at immunohistologic staining with antidextran antibody.
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When LCDIO internalization was plotted against tumor cell growth rate, a positive linear correlation (r = 0.929) between the two parameters was observed (Fig 4). The faster the growth rate, the greater the LCDIO uptake, an observation that may be related to the higher endocytosis rate in the faster-proliferating cells. Endothelial cells also showed LCDIO uptake; however, it is unclear whether the relatively high uptake was related to cellular proliferation, and future studies with quiescent endothelial cell populations are in progress. Finally, nondividing differentiated cells such as lymphocytes showed the lowest amount of cellular uptake.
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DISCUSSION |
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Reticuloendothelial System Accumulation versus Tumoral Accumulation
In early studies (21), the primary distribution of iron oxide was shown to be in the reticuloendothelial system in liver, spleen, bone marrow, and other reticuloendothelial system–containing organs. With the introduction of smaller and long-circulating iron oxides, this distribution was shown to be different, with less uptake in liver and spleen and concomitantly more uptake in lymph nodes (7). It was not until the introduction of long-circulating particles (2), however, that tumoral uptake also was observed (10,12), particularly when used at higher doses.
Until now, to our knowledge, there have been no comprehensive studies of the mechanism and magnitude of tumoral LCDIO accumulation. Our current data allow quantification and comparison of organ distributions with a model LCDIO probe in a brain tumor model. The data support even seemingly contradictory imaging findings: Although there was an unequivocal distribution of LCDIO to tumors, the overall accumulation was relatively low and was dependent on tumor location. In brain tumors, accumulation was 0.11% of the injected dose per gram of tissue, which was 10-fold higher than that in adjacent normal brain. Because of this difference in distribution (and presumably changes in relaxivity of cell-internalized LCDIO), the signal intensity of brain tumors was changed (10). In cases of subcutaneous tumors, we have found that LCDIO accumulation was 1.1% of injected dose per gram of tissue (unpublished data, 1998), which makes this agent useful as an experimental magnetic label for MR imaging of solid tumors.
LCDIO in Tumoral Macroenvironments
LCDIO accumulated preferentially in the tumoral periphery and heterogeneously throughout the remainder of the tumor. This heterogeneity was correlated with the presence of vessels within individual histologic sections and was in accordance with other observations (20) of preferential peripheral extravasation of a fluorescent macromolecule in tumors. The particles were positively identified at fluorescence microscopy or on immunohistochemically stained specimens in several cell populations, including endothelial cells, tumor-associated macrophages, and tumor cells. For these reasons and because LCDIO nanoparticles may transcytose in endothelial cells to achieve access to tumoral interstitium (22), it is not surprising that a small fraction of the agent was present in endothelial cells.
Neoplasms typically are infiltrated by macrophages derived from monocytes recruited from the circulation, and these cells represent another target population that avidly internalizes LCDIO (23–25). In recent studies, the degree of intratumoral infiltration and distribution of phagocytic cells has been shown to be a function of different factors, such as expression of monocyte chemoattractant protein–1 (26), in situ production of cytokines (27), and stage of tumor development and angiogenesis (28,29). Macrophages can constitute as much as 40%–60% of the tumor mass but typically are present in lower amounts (20%–30%) in gliomas (24). Our results are in accordance with these observations and showed that 20.9% ± 0.1 of all tumoral LCDIO accumulated in tumor-associated macrophages.
LCDIO Distribution in the Cellular Environment
The bulk of intracellular LCDIO particles in tumors was present inside tumor cells, an observation that brings up several questions: (a) What are the mechanisms of uptake and what are they related to; (b) where is LCDIO stored intracellularly; and (c) what magnetic changes in the particles may occur during cellular uptake? Cellular uptake data, as well as other data (13), showed that uptake was ubiquitous in different tumor cells and was not saturable, which suggests that fluid-phase (rather than receptor-mediated) endocytosis is the mechanism of uptake. More important, the current results showed that there was a positive correlation between cellular LCDIO uptake and tumor doubling time (Fig 4). This observation confirms our preliminary results obtained with synchronized tumor cell culture (unpublished data, 1998), which indicate that endocytosis is regulated by the cellular cycle. More extensive studies are currently underway to provide independent corroboration of this finding. This correlation is important because cellular internalization of LCDIO changes the relaxivity of the particle, and this effect can be visualized at MR imaging. In a prior study (30), it was shown that the R2:R1 ratio of relaxation rates for MR imaging with LCDIO changes from 2.1 (in solution [eg, interstitium]) to 13.0 on internalization, all due to compartmentalization in a model membrane-enclosed compartment. We believe it should, therefore, be possible to use this method to indirectly image proliferating cells in whole tumors. Such a new imaging technique could have far-reaching implications for cancer diagnosis and therapy.
In summary, the current results bring together several key observations with regard to the biologic properties of long-circulating iron oxide in tumors. The current study was possible because of (a) the development of a genetically engineered cell line that enabled triple-label fluorescence microscopy and (b) the establishment of antidextran antibody immunohistologic analysis methods. We believe that the results form the basis for further exploration of the correlation between tumoral growth kinetics and LCDIO-induced relaxivity changes. The results are also applicable to the future development of targeted MR image enhancement agents (1) and the experimental study of the biologic characteristics of tumors.Practical application: Tumoral LCDIO accumulation is not negligible and explains signal intensity changes on clinical MR studies. These changes can be observed in primary and metastatic tumors and reflect particle uptake into tumor cells, as well as into tumor-associated macrophages. Because uptake into tumor cells seems to correlate with proliferation, MR imaging may become a method for the study of in vivo growth kinetics.
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Acknowledgments |
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Footnotes |
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Author contributions: Guarantors of integrity of entire study, A.M., R.W.; study concepts, A.M., R.W.; study design, all authors; definition of intellectual content, all authors; literature research, A.M., A.B., R.W.; experimental studies, all authors; data acquisition and analysis, A.M., E.M.; statistical analysis, A.M., E.M.; manuscript preparation, A.M., R.W.; manuscript editing, R.W.; manuscript review, all authors.
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TOPAbstractIntroductionMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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