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Experimental Therapeutics |
vß3 Integrin Binding Peptides in a Nude Mouse Model
Departments of Nuclear Medicine [M. L. J., I. D., W. J. O., C. F., F. H. C., O. C. B.] and Obstetrics and Gynecology [M. L. J., L. F. M., H. B.], University Medical Center Nijmegen, 6500 HB Nijmegen, the Netherlands, and Bristol-Myers Squibb, Billerica, Massachusetts 01862 [D. S. E., M. R.]
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ABSTRACT |
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vß3 integrin is expressed on proliferating endothelial cells such as those present in growing tumors, as well as on tumor cells of various origin. Tumor-induced angiogenesis can be blocked in vivo by antagonizing the vß3 integrin with small peptides containing the Arg-Gly-Asp (RGD) amino acid sequence. This tripeptidic sequence, naturally present in extracellular matrix proteins, is the primary binding site of the vß3 integrin. Because of selective expression of vß3 integrin in tumors, radiolabeled RGD peptides are attractive candidates for vß3 integrin targeting in tumors. We studied the in vivo behavior of the radiolabeled dimeric RGD peptide E-[c(RGDfK)]2 in the NIH:OVCAR-3 s.c. ovarian carcinoma xenograft model in BALB/c nude mice. Conjugation of the 1,4,7,10-tetraazadodecane-N,N',N'',N'''-tetraacetic acid (DOTA) and hydrazinonicotinamide (HYNIC) chelators enabled efficient radiolabeling with 111In/90Y and 99mTc, respectively. The radiolabeled peptide was rapidly excreted renally. Uptake in nontarget organs such as liver and spleen was considerable. Tumor uptake peaked at 7.5% injected dose (ID)/g (111In-DOTA-E-[c(RGDfK)]2) or 6.0%ID/g (99mTc-HYNIC-E-[c(RGDfK)]2) at 2 and 1 h postinjection, respectively. Integrin vß3 receptor binding specificity was demonstrated by reduced tumor uptake after injection of the scrambled control peptide 111In-DOTA-E-[c(RDKfD)]2 (0.28%ID/g at 2 h p.i.) and after coinjection of excess nonradioactive 115In-DOTA-E-[c(RGDfK)]2 (0.22%ID/g at 2 h p.i.). A single injection of 90Y-DOTA-E-[c(RGDfK)]2 at the maximum-tolerated dose (37 MBq) in mice with small s.c. tumors caused a significant growth delay as compared with mice treated with 37 MBq 90Y-labeled scrambled peptide or untreated mice (median survival of 54 versus 33.5 versus 19 days, respectively). In conclusion, the radiolabeled RGD peptides 111In-DOTA-E-[c(RGDfK)]2 and 99mTc-HYNIC-E-[c(RGDfK)]2 demonstrated high and specific tumor uptake in a human tumor xenograft. Injection of 90Y-DOTA-E-[c(RGDfK)]2 induced a significant delay in tumor growth. Potentially, these peptides can be used for peptide receptor radionuclide imaging as well as therapy. |
INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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-subunit and a ß-subunit. Integrin vß3 is expressed on proliferating but not on quiescent endothelial cells. In addition, vß3 can be found on tumor cells of various origin. Integrin vß3 mediates cellular adhesion to vitronectin, fibrinogen, laminin, collagen, von Willebrand factor, or osteopontin through their exposed RGD2
amino acid sequence (2)
. Integrin vß3-mediated cell adhesion may affect cell cycle kinetics or may cause anchorage-dependent cell death or apoptosis.
Because it has been recognized that the growth of virtually all solid tumors is dependent on angiogenesis, studies have focused on agents that could inhibit this process (3)
. It was found that a monoclonal antibody directed toward the vß3 integrin blocked angiogenesis in human melanoma and breast tumor xenografts (4)
without affecting pre-existing blood vessels (5)
. Similar effects could be achieved with small peptides containing the RGD amino acid sequence (6
, 7)
. Because of its highly restricted expression and its vital role in angiogenesis, the vß3 integrin is an attractive candidate in anticancer strategies.
Radiolabeled receptor-binding peptides have emerged as an important class of radiopharmaceuticals (8)
. Recently, several studies reported the development of radiolabeled RGD peptides for vß3 integrin receptor targeting (9, 10, 11, 12, 13, 14)
. In animal experiments, specific tumor targeting was reported in mice with melanoma, breast, and osteosarcoma cancer (10
, 13
, 14)
and in rats with pancreatic tumors (11)
.
Here we studied the tumor targeting potential of both a 111In- and 99mTc-radiolabeled dimeric RGD peptide, derivatized with the chelators DOTA and HYNIC, in a s.c. ovarian carcinoma xenograft mouse model. In addition, the therapeutic potential of the 90Y-labeled RGD peptide was assessed.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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vß3 integrin (IC50 = 0.9 nM) and a low affinity for the vß5 and IIBß3 integrin (IC50 > 10 nM) (15)
. The compound was derivatized with the chelators DOTA (Fig. 1)
or HYNIC to allow labeling of the peptide with 111In/90Y or 99mTc/188Re, respectively. A DOTA-conjugated peptide with the scrambled amino acid sequence E-[c(RGKfD)]2 was used as a control peptide in these studies.
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90Y-DOTA-E-[c(RGDfK)]2 (RP697; Bristol-Myers Squibb) was prepared by adding 740 MBq 90YCl3 (NEN, Boston, MA) to 100 µg of DOTA-E-[c(RGDfK)]2 dissolved in 450 µl of 0.25 M ammoniumacetate buffer (pH 7.0). Again the mixture was heated at 100°C for 15 min. Quality control was carried out as described for the 111In-labeled peptide.
HYNIC-E-[c(RGDfK)]2 was radiolabeled with 99mTc to obtain 99mTc-HYNIC-E-[c(RGDfK)]2 (RP593; Dupont, Billerica, MA). Briefly, 20 µg of HYNIC-E-[c(RGDfK)]2 was dissolved in 200 µl of 0.25 M succinate buffer (pH 5.0). Then 6.5 mg of tris(hydroxymethyl)methylglycine (Fluka, Buchs, Switzerland) and 5 mg of triphenylphosphine-3,3',3''-trisulfonate (Sigma, St. Louis, MO) were added in 500 µl water. After adding 0.85 GBq 99mTcO4-, the reaction mixture was heated at 100°C for 15 min. RCP was checked as described above. For the RP-HPLC procedure, a gradient of 12–15% acetonitrile in 25 mM phosphate buffer (pH 6.0), over 30 min, was used at a flow rate of 1.0 ml/min. The vß3 binding capacity of the radiolabeled peptides was confirmed in an in vitro cell binding assay. IGROV-1 cells were trypsinized and preincubated in Tris-HCl (pH 7.4) supplemented with 1 mM MgCl2, 1 mM CaCl2, 1 mM MnCl2, and 1% BSA for 15 min at 0°C. A fixed amount of radiolabeled peptide (105 cpm) was incubated with increasing cell concentrations (1.2 x 107-2 x 108 cells/ml, 0.5 ml/incubation) in RPMI medium (Life Technologies, Inc., Breda, the Netherlands) supplemented with 0.5% BSA and 0.05% NaN3. Nonspecific binding was determined by coincubating an excess of unlabeled peptide. The receptor binding fraction of the radiolabeled peptides at infinite cell concentration, as derived from the modified Lineweaver-Burke plot, exceeded 70%.
Animal Model.
A cell suspension of NIH:OVCAR-3 ovarian carcinoma cells was prepared (108 cells/ml). A total of 0.1 ml of the cell suspension was injected s.c. in the right upper flank of 6–8-week-old female nude BALB/c mice. Two weeks after inoculation of the tumor cells, when tumors weighed 0.1–0.4 g, mice received injections of the 111In or the 99mTc-labeled peptides. The therapeutic doses of 90Y-labeled peptides were injected 12 days after inoculation. The studies were approved by the local Animal Welfare Committee. The NIH:OVCAR-3 cells express the vß3 integrin as determined by flowcytometric analysis after staining with a murine monoclonal antibody against vß3 (LM609).
Biodistribution Studies.
In all experiments, 5 mice/time point were used, and 370 kBq 111In-DOTA-E-[c(RGDfK)]2 (0.5 µg) or 1.7 MBq 99mTc-HYNIC-E-[c(RGDfK)]2 (0.04 µg) were i.v. injected. One, 2, 4, 8, and 24 h after injection of 111In-DOTA-E-[c(RGDfK)]2 and 99mTc-HYNIC-E-[c(RGDfK)]2, mice were anesthetized with ether. After blood was collected from the retro-orbital venous plexus, mice were killed by cervical dislocation. Tissues (tumor, muscle, lung, spleen, kidney, liver, small intestine) were dissected and weighed. The activity in tissues and injection standards was measured in a shielded well-type scintillation gamma counter (Wizard, Pharmacia, Turku, Finland) and expressed as the percentage of the injected dose/gram tissue (%ID/g). Using these data, tumor-to-blood ratios were calculated.
Scintigraphic Imaging.
Mice with s.c. NIH:OVCAR-3 tumors (0.5 g) were anesthetized by enflurane inhalation anesthesia and placed prone on a single head gamma camera equipped with a parallel hole medium energy collimator (Siemens Orbiter; Siemens, Inc., Hoffman Estate, IL). Images were acquired 2 h after injection of 1.8 MBq 111In-labeled peptides and stored digitally in a 256 x 256 matrix.
Receptor Specificity Studies.
The receptor-mediated localization of the 111In-labeled RGD peptide was investigated by determining the biodistribution of 111In-DOTA-E-[c(RGDfK)]2 in mice with OVCAR-3 tumors in the presence or absence of a 1000-fold excess of nonradioactive 115In-DOTA-E-[c(RGDfK)]2. Biodistribution of the radiolabel was determined as described above at 2 h p.i. in 5 mice/group. In an additional experiment, the biodistribution of 111In-DOTA-E-[c(RGDfK)]2 was compared with that of the scrambled peptide 111In-DOTA-E-[c(RGKfD)]2. The peptide dose of both peptides was 0.5 µg, and the biodistribution of the radiolabel was determined as described above at 30 min, 1, 2 and 4 h p.i.
MTD of 90Y-DOTA-E-[c(RGDfK)]2.
The MTD in nontumor-bearing female nude BALB/c mice was determined by i.v. injection of escalating activities of 90Y-DOTA-E-[c(RGDfK)]2. Each dose was tested in three mice. The doses tested were 22, 30, 37, 44, and 52 MBq 90Y-DOTA-E-[c(RGDfK)]2/mouse. Body weight and survival of the mice were monitored twice weekly during the whole observation period. Peripheral blood counts were checked once weekly for 3 weeks together with blood creatinine and blood ureum nitrogen. The MTD was set on the dose below the first dose that caused severe loss of body weight (>20%) or death of one or more animals of a dose group.
Peptide Receptor Radionuclide Therapy.
Mice with s.c. OVCAR-3 tumors received 37 MBq 90Y-DOTA-E-[c(RGDfK)]2 or 37 MBq 90Y-DOTA-E-[c(RGKfD)]2. A group of mice that did not receive any treatment served as control group. The size of the tumors was measured twice weekly in three dimensions using a caliper. The volume was estimated assuming the tumors were elipsoids using the formula: volume = 4/3 
(1/2 length x 1/2 width x 1/2 height). At the time of the injection, the volume of the s.c. tumors ranged from 27 to 150 mm3. At least 7 mice/experimental group were used.
Statistical Analysis.
Statistical analysis was performed using GraphPad Prism 3.0 (GraphPad Software, San Diego, CA). The biodistribution data were analyzed using the one-way ANOVA test. The level of significance was set at P = 0.05.
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RESULTS |
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. 99mTc-HYNIC-E-[c(RGDfK)]2 typically revealed two symmetric peaks at 17 and 20 min (Fig. 2)
, representing the two diastereomers of the compound (16)
. The RCP of 99mTc-HYNIC-E-[c(RGDfK)]2, 111In-DOTA-E-[c(RGKfD)]2, 90Y-DOTA-E-[c(RGDfK)]2, and 90Y-DOTA-E-[c(RGKfD)]2 also exceeded 90%. Minor impurities were observed in the elution profile with a retention time of 
10 min.
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. The s.c. tumors were visualized on the images of the mice that received 111In-DOTA-E-[c(RGDfK)]2 but not on the images of mice that received injections of 111In-DOTA-E-[c(RGKfD)]2.
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. After injection of both agents, the radioactivity cleared rapidly from the blood. Uptake of the radiolabeled peptides in the tumor was rapid and high. The highest uptake in the tumor was obtained with 111In-DOTA-E-[c(RGDfK)]2 at 2 h p.i. at 7.5%ID/g, whereas the highest tumor uptake of 99mTc-HYNIC-E-[c(RGDfK)]2 was found at 1 h p.i. at 6.0%ID/g. In the course of time, the tumor-to-blood ratios rose up to 92 for 111In-DOTA-E-[c(RGDfK)]2 and 26 for 99mTc-HYNIC-E-[c(RGDfK)]2. Remarkably, there was considerable uptake of both peptides in various normal tissues such as spleen, liver, and kidney. Muscle and lung tissues had relatively low activity uptake.
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. Uptake in the tumor was reduced most pronouncedly from 5.2 to 0.2%ID/g. The control peptide 111In-DOTA-E-[c(RGKfD)]2 showed a biodistribution profile highly similar to that of 111In-DOTA-E-[c(RGDfK)]2 in the presence of an excess 115In-DOTA-E-[c(RGDfK)]2 (Fig. 6)
. Uptake of the scrambled peptide in the tumor was similarly low (0.3%ID/g, 1 h p.i.). Both experiments showed that the uptake and retention of 111In-DOTA-E-[c(RGDfK)]2 were receptor dependent in the tumor but also in several normal organs such as the spleen and the liver.
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. After injection of 44 and 52 MBq 90Y-DOTA-E-[c(RGDfK)]2, the body weight of the mice rapidly fell <90% of the initial value. MTD was therefore set on 37 MBq 90Y-DOTA-E-[c(RGDfK)]2. The mice that received the highest activity doses showed a marked decrease in their hemoglobin levels as early as 5 days after injection. During the first 3 weeks p.i., there was no indication of severe bone marrow suppression (Fig. 7, B–D)
nor of abnormal kidney function (creatine and blood ureum nitrogen levels were normal at all time points; data not shown).
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. The tumor volume doubling time in the group that received 37 MBq of the vß3-binding peptide was 5.2 days, as compared with 3.9 days in the group that received 37 MBq of the scrambled peptide. The tumor volume doubling time of the mice that did not receive any treatment was 3.2 days. In 50% of mice treated with 37 MBq 90Y-DOTA-E-[c(RGDfK)]2, the size of the s.c. tumor exceeded 1.0 cm3 after 54 days compared with 34 days for the group treated with the scrambled peptide (DOTA-E-[c(RGDfK)]2) labeled with the same activity dose of 90Y. In the group of mice that did not receive any treatment, the volume of 50% of the tumors exceeded 1.0 cm3 after 19 days. Tumor growth in the three groups was significantly different (90Y-DOTA-E-[c(RGDfK)]2 versus 90Y-DOTA-E-[c(RGKfD)]2: P < 0.05; 90Y-DOTA-E-[c(RGDfK)]2 versus control: P < 0.01; 90Y-DOTA-E-[c(RGKfD)]2 versus controls: P < 0.05). In a separate experiment, it was established that an i.v. injection with the unlabeled DOTA-E-[c(RGDfK)]2 peptide did not have any therapeutic effect in this model: the median survival of the mice that received 5 µg of unlabeled DOTA-E-[c(RGDfK)]2 (19 days) was similar to that of mice that received injections with saline (15 days; P > 0.05).
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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vß3 integrin was demonstrated. Finally, peptide receptor radionuclide therapy using 90Y-DOTA-E-[c(RGDfK)]2 caused a significant delay of growth of small tumors in mice.
Other authors have shown that radiolabelled RGD peptides can accumulate in animal model tumors. The iodinated monomeric RGD peptide c(RGDyV) targeted M21 melanoma, osteosarcoma, and MaCaF breast carcinoma tumors, with a tumor uptake of up to 3.50%ID/g at 10 min p.i. (13)
. However, this peptide cleared via the hepatobiliary route, as indicated by high uptake in liver and intestines. By substituting the amino acid valine by a lysine and conjugating a hydrophilic sugar moiety to this amino acid, the peptide cleared renally (10)
. A similar phenomenon was recently described with the cyclic peptide c(RGDyK). This radioiodinated peptide cleared via the hepatobiliary route. However, when the 
-amino group of the lysine residue was substituted with diethylenetriaminepentaacetic acid to allow labeling of the peptide with 111In, the peptide cleared exclusively via the kidneys. In a rat model, this 111In-labeled peptide showed preferential tumor accumulation in syngeneic CA20948 pancreatic tumors (11)
. Our DOTA, as well as HYNIC-conjugated radiolabeled peptides, almost exclusively cleared via the preferred renal pathway.
Several nontumor tissues such as liver and spleen also showed vß3 integrin receptor-mediated uptake, suggesting that the peptide also binds specifically to a cell surface molecule expressed on these tissues. However, to our knowledge, the expression of vß3 integrin in these murine tissues has not been documented. Recently, vß3 expression in microvessels of the lung and, to a lesser extent, the liver of the rat has been documented (17)
. Localization of the radiolabeled peptides in nontumor tissues may limit their imaging, as well as their therapeutic application. The physiological uptake in the liver, spleen, and kidneys may hamper imaging of abdominal tumor lesions and will limit the activity dose that can be administered safely. Future studies will have to show whether this phenomenon also plays a role in other species or whether this interaction can be prevented by modifying the structure of the peptide.
We found marked differences in the biodistribution of 111In-DOTA-E-[c(RGDfK)]2 as compared with the 99mTc-HYNIC-E-[c(RGDfK)]2 peptide. In particular, the blood level and the uptake in the kidneys were higher for the 99mTc-labeled peptide. It has been shown that the blood level of a peptide can be markedly affected by the chelator and even by the coligand of the radiolabeled peptide: interaction of HYNIC-Tc-coligand complex with serum proteins has been described and this interaction may affect the circulatory half-life and the biodistribution of the radiolabeled compound (18) . This may explain the higher blood level of 99mTc-HYNIC-[c(RGDfK)]2 as compared with the 111In-labeled peptide. The enhanced kidney retention of the 99mTc-labeled peptide may be attributable to the more effective reabsorption of this peptide by the tubular cells. After glomerular filtration, small peptides are reabsorbed from the primary urine by the tubular cells (19) . It has been hypothesized that peptides adhere to the luminal surface of the tubular cells by electrostatic interaction: the peptide may bind via its positive charges to the negatively charged receptors on the tubular cell membrane. Subsequently, the peptide is internalized by receptor-mediated endocytosis, and the radiolabeled peptide is degraded in lysosomes. The DOTA-conjugated peptide may present less positive charges as compared with the HYNIC-conjugated peptide, and this may explain the difference in renal uptake of the two peptides.
In addition, it remains to be determined whether RGD peptides are retained in tumor tissue because of the interaction with vß3 integrin expressed on the neovasculature or on the tumor cells or on a combination of both cell types. In this respect, it is unclear whether RGD peptides actually target angiogenesis in growing tumors or vß3 expression of tumor cells.
This is the first report on the therapeutic potential of radiolabeled RGD peptides in mice. We showed that the 90Y-labeled DOTA-E-[c(RGDfK)]2 peptide induced a significant delay in the growth of a s.c. human ovarian carcinoma xenograft. Our preliminary studies suggest that the approach is particularly effective against relatively small tumors (<150 mm3). Small peptides labeled with ß-emitting radionuclides may cause a high radiation dose to the kidneys. However the 111In-labeled RGD peptide showed relatively low retention in the kidneys. Although the kidneys are relatively radiation resistant, irreversible radiation damage of kidney function may occur at high radiation doses. In external beam radiotherapy, a dose of 23 Gy (2300 rad) is considered the maximum-tolerated radiation dose to the kidneys. The radiation dose to the kidneys from internal radionuclide therapy that does not give rise to any (acute or chronic) nephrotoxicity is still a matter of debate (20)
. The choice of the radionuclide, more specifically the range of the emitted particles in tissue, is an important factor that may affect the renal toxicity of the radiolabeled peptide. Our future studies will focus on the selection of the most optimal radionuclide for peptide receptor radionuclide therapy with RGD peptides. Besides ß-emitters like 188Re, 177Lu, and 67Cu, also -emitters (213Bi) as well as Auger emitters (111In, 67Ga) could be considered.
In conclusion, these studies indicate that peptide radionuclide receptor therapy based on the targeting of the vß3 integrin by radiolabeled RGD peptides causes a significant growth delay in a s.c. xenograft mouse model. Optimization of this therapy by increasing the number of injections and the choice of radionuclide could further improve the therapeutic potential of the peptides.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 To whom requests for reprints should be addressed, at Department of Nuclear Medicine, UMC Nijmegen, P. O. Box 9101, 6500 HB Nijmegen, the Netherlands. 
2 The abbreviations used are: RGD, Arg-Gly-Asp; DOTA, 1,4,7,10-tetraazadodecane-N,N',N'',N'''-tetraacetic acid; HYNIC, hydrazinonicotinamide; RCP, radiochemical purity; RP-HPLC, reversed phase high-performance liquid chromatography; MTD, maximum-tolerated dose; p.i., postinjection.
Received 11/19/01. Accepted 8/27/02.
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X. Zhang, Z. Xiong, Y. Wu, W. Cai, J. R. Tseng, S. S. Gambhir, and X. Chen Quantitative PET Imaging of Tumor Integrin {alpha}v{beta}3 Expression with 18F-FRGD2 J. Nucl. Med., January 1, 2006; 47(1): 113 - 121. [Abstract] [Full Text] [PDF]
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H.-J. Wester and H. Kessler Molecular Targeting with Peptides or Peptide-Polymer Conjugates: Just a Question of Size? J. Nucl. Med., December 1, 2005; 46(12): 1940 - 1945. [Full Text] [PDF]
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Y. Wu, X. Zhang, Z. Xiong, Z. Cheng, D. R. Fisher, S. Liu, S. S. Gambhir, and X. Chen microPET Imaging of Glioma Integrin {alpha}v{beta}3 Expression Using 64Cu-Labeled Tetrameric RGD Peptide J. Nucl. Med., October 1, 2005; 46(10): 1707 - 1718. [Abstract] [Full Text] [PDF]
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I. Roodink, J. Raats, B. van der Zwaag, K. Verrijp, B. Kusters, H. van Bokhoven, M. Linkels, R. M.W. de Waal, and W. P.J. Leenders Plexin D1 Expression Is Induced on Tumor Vasculature and Tumor Cells: A Novel Target for Diagnosis and Therapy? Cancer Res., September 15, 2005; 65(18): 8317 - 8323. [Abstract] [Full Text] [PDF]
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 V. Askoxylakis, S. Zitzmann, W. Mier, K. Graham, S. Kramer, F. von Wegner, R. H.A. Fink, M. Schwab, M. Eisenhut, and U. Haberkorn Preclinical Evaluation of the Breast Cancer Cell-Binding Peptide, p160 Clin. Cancer Res., September 15, 2005; 11(18): 6705 - 6712. [Abstract] [Full Text] [PDF]
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B. R. Line, A. Mitra, A. Nan, and H. Ghandehari Targeting Tumor Angiogenesis: Comparison of Peptide and Polymer-Peptide Conjugates J. Nucl. Med., September 1, 2005; 46(9): 1552 - 1560. [Abstract] [Full Text] [PDF]
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 S. Achilefu, S. Bloch, M. A. Markiewicz, T. Zhong, Y. Ye, R. B. Dorshow, B. Chance, and K. Liang Synergistic effects of light-emitting probes and peptides for targeting and monitoring integrin expression PNAS, May 31, 2005; 102(22): 7976 - 7981. [Abstract] [Full Text] [PDF]
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 T. A. Rege, C. Y. Fears, and C. L. Gladson Endogenous inhibitors of angiogenesis in malignant gliomas: Nature's antiangiogenic therapy Neuro-oncol, April 1, 2005; 7(2): 106 - 121. [Abstract] [PDF]
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K.-H. Lee, K.-H. Jung, S.-H. Song, D. H. Kim, B. C. Lee, H. J. Sung, Y.-M. Han, Y. S. Choe, D. Y. Chi, and B.-T. Kim Radiolabeled RGD Uptake and {alpha}v Integrin Expression Is Enhanced in Ischemic Murine Hindlimbs J. Nucl. Med., March 1, 2005; 46(3): 472 - 478. [Abstract] [Full Text] [PDF]
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M. R. Lewis Radiolabeled RGD Peptides Move Beyond Cancer: PET Imaging of Delayed-Type Hypersensitivity Reaction J. Nucl. Med., January 1, 2005; 46(1): 2 - 4. [Full Text] [PDF]
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D. J. Burkhart, B. T. Kalet, M. P. Coleman, G. C. Post, and T. H. Koch Doxorubicin-formaldehyde conjugates targeting {alpha}v{beta}3 integrin Mol. Cancer Ther., December 1, 2004; 3(12): 1593 - 1604. [Abstract] [Full Text] [PDF]
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 R. M. Schiffelers, A. Ansari, J. Xu, Q. Zhou, Q. Tang, G. Storm, G. Molema, P. Y. Lu, P. V. Scaria, and M. C. Woodle Cancer siRNA therapy by tumor selective delivery with ligand-targeted sterically stabilized nanoparticle Nucleic Acids Res., November 1, 2004; 32(19): e149 - e149. [Abstract] [Full Text] [PDF]
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X. Chen, P. S. Conti, and R. A. Moats In vivo Near-Infrared Fluorescence Imaging of Integrin {alpha}v{beta}3 in Brain Tumor Xenografts Cancer Res., November 1, 2004; 64(21): 8009 - 8014. [Abstract] [Full Text] [PDF]
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M. Mikawa, H. Wang, L. Guo, R. Liu, J. Marik, Y. Takada, K. Lam, and D. Lau Novel peptide ligands for integrin {alpha}4{beta}1 overexpressed in cancer cells Mol. Cancer Ther., October 1, 2004; 3(10): 1329 - 1334. [Abstract] [Full Text] [PDF]
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F. G. Blankenberg, S. Mandl, Y.-A. Cao, C. O'Connell-Rodwell, C. Contag, C. Mari, T. I. Gaynutdinov, J.-L. Vanderheyden, M. V. Backer, and J. M. Backer Tumor Imaging Using a Standardized Radiolabeled Adapter Protein Docked to Vascular Endothelial Growth Factor J. Nucl. Med., August 1, 2004; 45(8): 1373 - 1380. [Abstract] [Full Text] [PDF]
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 P. Holig, M. Bach, T. Volkel, T. Nahde, S. Hoffmann, R. Muller, and R. E. Kontermann Novel RGD lipopeptides for the targeting of liposomes to integrin-expressing endothelial and melanoma cells Protein Eng. Des. Sel., May 1, 2004; 17(5): 433 - 441. [Abstract] [Full Text] [PDF]
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