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Dextran graft poly (N-methacryloylglycylglycine) copolymer-tyrosine conjugates (dextran-g-PMAGGCONHTyr) were synthesized and characterized. Dynamic light scattering (DLS) results indicated that the graft copolymers are soluble in pH 7.4 PBS and 0.9% saline solutions. The graft copolymers were labeled with (125)I, and the labeling stability in 0.9% saline solution was investigated. Pharmacokinetics studies showed a rapid clearance of (125)I-labeled graft copolymers from the blood pool. Biodistribution images confirmed the preferable liver and spleen accumulation within 1 h after injection and rapid clearance from all the organs over time. The graft copolymer with molecular weight of 9.8 kDa was eliminated from the kidney significantly faster than those with higher molecular weight. The effect of the numbers of -COOH groups on the graft copolymers on the biodistribution was also investigated. It was found that the graft copolymers with the average number of -COOH groups per glucopyranose unit (DS(-COOH)) of 0.57 and 0.18 are mainly distributed in liver and spleen at 1 h after injection, whereas the graft copolymer with DS(-COOH) of 0.07 is mainly accumulated in kidney.

http://dx.doi.org/10.1021/bm200194s

Targeted radionuclide therapy, which is based on the selective delivery of a sufficient radiation dose to tumors without significantly affecting normal tissues, is a promising therapeutic approach for the treatment of a wide variety of malignancies. Integrins, a family of cell adhesion molecules, play key roles during tumor angiogenesis and metastasis. Among all the integrins, αvβ3 seems to be the most important in the process of tumor angiogenesis. Integrin αvβ3 is highly expressed on activated endothelial cells, new-born vessels as well as some tumor cells, but is not present in resting endothelial cells and most normal organ systems, making it a suitable target for anti-tumor therapy. In this review, we summarize the current development and applications of antibody-, peptide-, and other ligand-based integrin targeted radiotherapeutics for tumor radiation therapy.

http://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21547160/

Positron emission tomography (PET) has become a powerful tool for probing biochemical processes in living subjects. PET imaging depends largely on the development of novel PET tracers labeled with positron-emitting radionuclides. Since the four traditional PET isotopes (18F, 11C, 13N, and 15O) are produced in a cyclotron and are short-lived, their use for long-term observation of biological processes in vivo is limited. In the last decades, extensive research in the development of other unconventional radionuclides (such as 64Cu, 68Ga, 89Zr, 86Y, and 124I) labeled tracers with half-lives complementary to the biological properties of their targeting agents has been conducted. Among these tracers, 86Y-based PET tracers have gained increasing attention since they are ideal surrogates for in vivo determination of biodistribution and dosimetry of therapeutic 90Y (pure β - emitter) pharmaceuticals. In this review article, we will brief introduce the physical characteristics, production, and radiochemistry of 86Y, and will summarize the current 86Y-based PET tracers used for molecular imaging and cancer detection in animal studies and in clinical trials.

http://www.eurekaselect.com/94484/article

Early evaluation of cancer response to a therapeutic regimen can help increase the effectiveness of treatment schemes and, by enabling early termination of ineffective treatments, minimize toxicity, and reduce expenses. Biomarkers that provide early indication of tumor therapy response are urgently needed. Solid tumors require blood vessels for growth, and new anti-angiogenic agents can act by preventing the development of a suitable blood supply to sustain tumor growth. The purpose of this study is to develop a class of novel molecular imaging probes that will predict tumor early response to an anti-angiogenic regimen with the humanized vascular endothelial growth factor antibody bevacizumab. Using a bevacizumab-sensitive LS174T colorectal cancer model and a 12-mer bacteriophage (phage) display peptide library, a bevacizumab-responsive peptide (BRP) was identified after six rounds of biopanning and tested in vitro and in vivo. This 12-mer peptide was metabolically stable and had low toxicity to both endothelial cells and tumor cells. Near-infrared dye IRDye800-labeled BRP phage showed strong binding to bevacizumab-treated tumors, but not to untreated control LS174T tumors. In addition, both IRDye800- and (18)F-labeled BRP peptide had significantly higher uptake in tumors treated with bevacizumab than in controls treated with phosphate-buffered saline. Ex vivo histopathology confirmed the specificity of the BRP peptide to bevacizumab-treated tumor vasculature. In summary, a novel 12-mer peptide BRP selected using phage display techniques allowed non-invasive visualization of early responses to anti-angiogenic treatment. Suitably labeled BRP peptide may be potentially useful pre-clinically and clinically for monitoring treatment response.

http://dx.doi.org/10.1007/s00726-010-0548-9

PURPOSE:

(99m)Tc-3PRGD(2) is a (99m)Tc-labeled dimeric cyclic RGD peptide with increased receptor binding affinity and improved kinetics for in vivo imaging of integrin α(v)β(3) expression in nude mouse model. To accelerate its clinical translation, we reported here the evaluation of the kit-formulated (99m)Tc-3PRGD(2) in healthy cynomolgus primates for its blood clearance kinetics, biodistribution, and radiation dosimetry.

PROCEDURES:

Healthy cynomolgus primates (4.1 ± 0.7 kg, n = 5) were anesthetized, and the venous blood samples were collected via a femoral vein catheter at various time points after injection of ~555 MBq of (99m)Tc-3PRGD(2). Serial whole-body scans were performed with a dual-head single photon emission computed tomography system after administering ~555 MBq of (99m)Tc-3PRGD(2) in the non-human primates, and the radiation dosimetry estimate was calculated.

RESULTS:

(99m)Tc-3PRGD(2) could be easily obtained from freeze-dried kits with high radiochemical purity (>95%) and high specific activity (~5 Ci/μmol). (99m)Tc-3PRGD(2) had a rapid blood clearance with less than 1% of the initial radioactivity remaining in the blood circulation at 60 min postinjection. No adverse reactions were observed up to 4 weeks after the repeated dosing. The whole-body images exhibited high kidney uptake of (99m)Tc-3PRGD(2) and high radioactivity accumulation in the bladder, demonstrating the rapid renal clearance of this tracer. The highest radiation doses of (99m)Tc-3PRGD(2) were found in the kidneys (13.2 ± 1.08 μGy/MBq) and the bladder wall (33.1 ± 1.91 μGy/MBq).

CONCLUSION:

(99m)Tc-3PRGD(2) can be readily available using the kit formulation. This tracer is safe and well tolerated, and no adverse events occurred in non-human primates. Further clinical testing and translation of (99m)Tc-3PRGD(2) for noninvasive imaging of integrin α(v)β(3) in humans are warranted.

http://dx.doi.org/10.1007/s11307-010-0385-y

We have recently developed a series of new Arg-Gly-Asp (RGD) dimeric peptides for specific targeting of integrin α(v)β₃ with enhanced tumor uptake and improved pharmacokinetics. In this study, we investigated ⁹⁰Y-labeled RGD tetramer (RGD4) and the new type of RGD dimer (3PRGD2), for the radionuclide therapy of integrin α(v)β₃-positive tumors. Biodistribution and gamma imaging studies of ¹¹¹In labeled RGD4 and 3PRGD2 were performed. Groups of nude mice were used to determine maximum tolerated dose (MTD) of ⁹⁰Y-DOTA-RGD4 and ⁹⁰Y-DOTA-3PRGD2. The radionuclide therapeutic efficacy of ⁹⁰Y-DOTA-RGD4 and ⁹⁰Y-DOTA-3PRGD2 was evaluated in U87MG tumor-bearing nude mice. The U87MG tumor uptake of ¹¹¹In-DOTA-3PRGD2 was slightly lower than that of the ¹¹¹In-DOTA-RGD4 (e.g., 6.13 ± 0.82%ID/g vs 6.43 ± 1.6%ID/g at 4 h postinjection), but the uptake of ¹¹¹In-DOTA-3PRGD2 in normal organs, such as liver and kidneys, was much lower than that of ¹¹¹In-DOTA-RGD4, which resulted in much higher tumor-to-nontumor ratios and lower toxicity. The MTD of ⁹⁰Y-DOTA-RGD4 in nude mice is less than 44.4 MBq, while the MTD of ⁹⁰Y-DOTA-3PRGD2 in mice is more than 55.5 MBq. ⁹⁰Y-DOTA-3PRGD2 administration exhibited a similar tumor inhibition effect as compared with ⁹⁰Y-DOTA-RGD4 at the same dose. The tumor vasculature in the ⁹⁰Y-DOTA-3PRGD2 treatment group was much less than the control groups. Radionuclide therapy studies exhibited that both ⁹⁰Y-DOTA-RGD4 and ⁹⁰Y-DOTA-3PRGD2 caused significant tumor growth delay in the U87MG tumor model. Compared to ⁹⁰Y-DOTA-RGD4, the low accumulation of ⁹⁰Y-DOTA-3PRGD2 in normal organs led to lower toxicity and higher MTD in nude mice, which would make it more suitable for high dose or multiple-dose regimens, in order to achieve maximum therapeutic efficacy.

http://dx.doi.org/10.1021/mp100403y

Dextran graft poly (N-methacryloylglycylglycine) copolymer-tyrosine conjugates (dextran-g-PMAGGCONHTyr) were synthesized and characterized. Dynamic light scattering (DLS) results indicated that the graft copolymers are soluble in pH 7.4 PBS and 0.9% saline solutions. The graft copolymers were labeled with (125)I, and the labeling stability in 0.9% saline solution was investigated. Pharmacokinetics studies showed a rapid clearance of (125)I-labeled graft copolymers from the blood pool. Biodistribution images confirmed the preferable liver and spleen accumulation within 1 h after injection and rapid clearance from all the organs over time. The graft copolymer with molecular weight of 9.8 kDa was eliminated from the kidney significantly faster than those with higher molecular weight. The effect of the numbers of -COOH groups on the graft copolymers on the biodistributionwas also investigated. It was found that the graft copolymers with the average number of -COOH groups per glucopyranose unit (DS(-COOH)) of 0.57 and 0.18 are mainly distributed in liver and spleen at 1 h after injection, whereas the graft copolymer with DS(-COOH) of 0.07 is mainly accumulatedin kidney.

http://dx.doi.org/10.1021/bm200194s

PURPOSE:

Targeting of integrin α(ν)β(3) with molecular imaging agents offers great potential in early detection and monitoring of tumour angiogenesis. Recently, an RGD (Arg-Gly-Asp) tracer, (99m)Tc-3P(4)-RGD(2), with high affinity to integrin α(ν)β(3) and in vivo tumour uptake was developed. In this study, we evaluate the feasibility of this novel radiotracer in the noninvasive differentiation of solitary pulmonary nodules (SPNs).

METHODS:

Twenty-one patients with SPNs on CT were studied scintigraphically after administration of (99m)Tc-3P(4)-RGD(2) with a dose of 939 ±  118 MBq. Image interpretation using a 5-point scale was performed by one thoracic radiologist for CT and three nuclear medicine radiologists for single photon emission computed tomography (SPECT). Scintigraphic images were also analysed semiquantitatively by calculating tumour to normal tissue ratio (T/N). The "gold standard" was based on the histopathological diagnosis of the surgical samples from all recruited patients. A fraction of the samples were analysed immunohistochemically for integrin α(v)β(3) expression.

RESULTS:

Among the 21 SPNs, 15 (71%) were diagnosed as malignant and 6 (29%) were benign. The mean size for SPNs was 2.2 ±  0.6 cm. The sensitivity and specificity for CT interpretation, SPECT visual and semiquantitative analysis were 80/67%, 100/67% and 100/67%, respectively. All SPNs classified as indeterminate by CT were correctly diagnosed by (99m)Tc-3P(4)-RGD(2) scintigraphy. The empirical receiver-operating characteristic (ROC) areas were 0.811 [95% confidence interval (CI) 58-95%] for CT, 0.833 (95% CI 61-96%) for SPECT and 0.844 (95% CI 62-96%) for T/N ratios, respectively. Immunohistochemistry confirmed α(ν)β(3) expression in malignant and benign nodules with uptake in (99m)Tc-3P(4)-RGD(2) scintigraphy.

CONCLUSION:

In this first-in-human study, we demonstrated the feasibility of using (99m)Tc-3P(4)-RGD(2) scintigraphy in differentiating SPNs. This procedure appears to be highly sensitive in detection of malignant SPNs. SPECT visual analysis seems to be sufficient for characterization of SPNs.

http://dx.doi.org/10.1007/s00259-011-1901-2

The peptide bombesin (BN) and derivates thereof show high binding affinity for the gastrin-releasing peptide receptor (GRPR), which is highly expressed in primary and metastasized prostate cancer. We have synthesized a new BN-based radiopharmaceutical (99m)technetium-HYNIC(tricine/TPPTS)-Aca-BN(7-14) ((99m)Tc-HABN) and evaluated its GRPR targeting properties in vitro and in a xenograft tumor model for humanprostate cancer in athymic mice. (99m)Tc-HABN was synthesized, and its lipophilicity and stability were investigated. The IC(50), internalization and efflux properties were determined in vitro using the GRPR expressing human prostate cancer cell line PC-3. (99m)Tc-HABN biodistribution andmicroSPECT imaging were performed in PC-3 tumor-bearing athymic mice. (99m)Tc-HABN was prepared with high labeling yield (>90%), high radiochemical purity (>95%) and a specific activity of ~19.8 MBq/nmol. The partition coefficient log D value was -1.60 ± 0.06. (99m)Tc-HABN proved to be stable in human serum for 6 h. The IC50 of HYNIC-Aca-BN(7-14) was 12.81 ± 0.14 nM. Incubation of PC-3 cells with (99m)Tc-HABN demonstrated rapid cellular internalization and a long intracellular retention time. When mice were injected with (99m)Tc-HABN, the activity was predominantly cleared via the kidneys. Uptake in the tumor was 2.24 ± 0.64% ID/g after 30 min, with a steady decrease during the 4 h study period. In vivo experiments with a blocking agent showed GRPR mediated uptake. (99m)Tc-HABN microSPECT imaging resulted in clear delineation of the tumor. (99m)Tc-HABN is a novel BN-based radiopharmaceutical that proved to be suitable for targeted imaging of prostate cancer with microSPECT using the human prostate cancer cell line PC-3 in a xenograft mouse model.

http://dx.doi.org/10.1021/mp200014h

The purpose of this study was to noninvasively monitor the therapeutic efficacy of cyclophosphamide (CTX) in a mouse model by dual-modalitymolecular imaging: positron emission tomography (PET) and bioluminescence imaging (BLI). Firefly luciferase (fLuc) transfected HCC-LM3-fLuc human hepatocellular carcinoma cells were injected subcutaneously into BALB/c nude mice to establish the experimental tumor model. Two groups of HCC-LM3-fLuc tumor-bearing mice (n  =  7 per group) were treated with saline or CTX (100 mg/kg on days 0, 2, 5, and 7). BLI and (18)F-fluorodeoxyglucose ((18)F-FDG) PET scans were done to evaluate the treatment efficacy. CTX induced a 25.25 ± 13.13% and 35.91 ± 25.85% tumorgrowth inhibition rate on days 9 and 12 posttreatment, respectively, as determined by BLI. A good linear correlation was found between the tumorsizes measured by caliper and the BLI signals determined by optical imaging (R(2)  =  .9216). (18)F-FDG imaging revealed a significant uptake reduction in the tumors of the CTX-treated group compared to that in the saline control group (5.30 ± 1.97 vs 3.00 ± 2.11% ID/g) on day 16 after CTX treatment. Dual-modality molecular imaging using BLI and small-animal PET can play important roles in the process of chemotherapy and will provide noninvasive and reliable monitoring of the therapeutic response.

http://dx.doi.org/10.2310/7290.2010.00041

Radiolabeled cyclic RGD (Arg-Gly-Asp) peptides represent a new class of radiotracers with potential for early tumor detection and noninvasive monitoring of tumor metastasis and therapeutic response in cancer patients. This article describes the synthesis of two cyclic RGD peptide dimer conjugates, DOTA-PEG(4)-E[PEG(4)-c(RGDfK)](2) (DOTA-3PEG(4)-dimer: DOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid; PEG(4) = 15-amino-4,7,10,13-tetraoxapentadecanoic acid) and DOTA-G(3)-E[G(3)-c(RGDfK)](2) (DOTA-3G(3)-dimer: G(3) = Gly-Gly-Gly). Integrin alpha(v)beta(3) binding affinities of cyclic RGD peptides were determined by competitive displacement of (125)I-echistatin bound to U87MG human glioma cells and follow the order of DOTA-E{E[c(RGDfK)](2)}(2) (DOTA-tetramer: IC(50) = 10 +/- 2 nM) > DOTA-3G(3)-dimer (IC(50) = 62 +/- 6 nM) approximately DOTA-3PEG(4)-dimer (IC(50) = 74 +/- 3 nM) > DOTA-E[c(RGDfK)](2) (DOTA-dimer: IC(50) = 102 +/- 5 nM). The addition of PEG(4) and G(3) linkers between two cyclic RGD motifs in DOTA-3G(3)-dimer and DOTA-3PEG(4)-dimer makes it possible for them to achieve the simultaneous integrin alpha(v)beta(3) binding in a bivalent fashion. Both (64)Cu(DOTA-3PEG(4)-dimer) and (64)Cu(DOTA-3G(3)-dimer) were prepared in high yield with specific activity being >50 Ci/mmol. Biodistribution and imaging studies were performed in athymic nude mice bearing U87MG human glioma xenografts. The results from those studies show that PEG(4) and G(3) linkers are particularly useful for improving tumor uptake and clearance kinetics of (64)Cu radiotracers from the nontumor organs, such as kidneys, liver, and lungs. There is a linear relationship between the tumor size and %ID tumor uptake, suggesting that (64)Cu(DOTA-3PEG(4)-dimer) and (64)Cu(DOTA-3PEG(4)-dimer) might be useful for noninvasive monitoring of tumor growth or shrinkage during antiangiogenic therapy. MicroPET imaging data clearly demonstrate the utility of (64)Cu(DOTA-3G(3)-dimer) as a new PET radiotracer for imaging integrin alpha(v)beta(3)-positive tumors.http://dx.doi.org/10.1007/s00726-009-0439-0

Porphyrin based photosensitizers are useful agents for photodynamic therapy (PDT) and fluorescence imaging of cancer. Porphyrins are also excellent metal chelators forming highly stable metallo-complexes making them efficient delivery vehicles for radioisotopes. Here we investigated the possibility of incorporating (64)Cu into a porphyrin-peptide-folate (PPF) probe developed previously as folate receptor (FR) targeted fluorescent/PDTagent, and evaluated the potential of turning the resulting (64)Cu-PPF into a positron emission tomography (PET) probe for cancer imaging. Noninvasive PET imaging followed by radioassay evaluated the tumor accumulation, pharmacokinetics and biodistribution of (64)Cu-PPF. (64)Cu-PPF uptake in FR-positive tumors was visible on small-animal PET images with high tumor-to-muscle ratio (8.88 ± 3.60) observed after 24 h. Competitive blocking studies confirmed the FR-mediated tracer uptake by the tumor. The ease of efficient (64)Cu-radiolabeling of PPF while retaining its favorable biodistribution, pharmacokinetics and selective tumor uptake, provides a robust strategy to transform tumor-targeted porphyrin-based photosensitizers into PET imaging probes.

http://www.thno.org/v01p0363.htm

PURPOSE:

The purpose of this study was to demonstrate the valence of cyclic RGD peptides, P-RGD (PEG(4)-c(RGDfK): PEG(4) = 15-amino-4,710,13-tetraoxapentadecanoic acid), P-RGD(2) (PEG(4)-E[c(RGDfK)](2), 2P-RGD(4) (E{PEG(4)-E[c(RGDfK)](2)}(2), 2P4G-RGD(4) (E{PEG(4)-E[G(3)-c(RGDfK)](2)}(2): G(3) = Gly-Gly-Gly) and 6P-RGD(4) (E{PEG(4)-E[PEG(4)-c(RGDfK)](2)}(2)) in binding to integrin α(v)β(3), and to assess the impact of peptide and linker multiplicity on biodistribution properties, excretion kinetics and metabolic stability of their corresponding (111)In radiotracers.

METHODS:

Five new RGD peptide conjugates (DOTA-P-RGD (DOTA =1,4,7,10-tetraazacyclododecane-1,4,7,10-tetracetic acid), DOTA-P-RGD(2), DOTA-2P-RGD(4), DOTA-2P4G-RGD(4), DOTA-6P-RGD(4)), and their (111)In complexes were prepared. The integrin α(v)β(3) binding affinity of cyclic RGD conjugates were determined by a competitive displacement assay against (125)I-c(RGDyK) bound to U87MG human glioma cells. Biodistribution, planar imaging and metabolism studies were performed in athymic nude mice bearing U87MG human glioma xenografts.

RESULTS:

The integrin α(v)β(3) binding affinity of RGD conjugates follows the order of: DOTA-6P-RGD(4) (IC(50) = 0.3 ± 0.1 nM) ~ DOTA-2P4G-RGD(4) (IC(50) = 0.2 ± 0.1 nM) ~ DOTA-2P-RGD(4) (IC(50) = 0.5 ± 0.1 nM) > DOTA-3P-RGD(2) (DOTA-PEG(4)-E[PEG(4)-c(RGDfK)](2): IC(50) = 1.5 ± 0.2 nM) > DOTA-P-RGD(2) (IC(50) = 5.0 ± 1.0 nM) >> DOTA-P-RGD (IC(50) = 44.3 ± 3.5 nM) ~ c(RGDfK) (IC(50) = 49.9 ± 5.5 nM) >> DOTA-6P-RGK(4) (IC(50) = 437 ± 35 nM). The fact that DOTA-6P-RGK(4) had much lower integrin α(v)β(3) binding affinity than DOTA-6P-RGD(4) suggests that the binding of DOTA-6P-RGD(4) to integrin α(v)β(3) is RGD-specific. This conclusion is consistent with the lower tumor uptake for (111)In(DOTA-6P-RGK(4)) than that for (111)In(DOTA-6P-RGD(4)). It was also found that the G(3) and PEG(4) linkers between RGD motifs have a significant impact on the integrin α(v)β(3)-targeting capability, biodistribution characteristics, excretion kinetics and metabolic stability of (111)In-labeled cyclic RGDpeptides.

CONCLUSION:

On the basis of their integrin α(v)β(3) binding affinity and tumor uptake of their corresponding (111)In radiotracers, it was conclude that 2P-RGD(4), 2P4G-RGD(4) and 6P-RGD(4) are most likely bivalent in binding to integrin α(v)β(3), and extra RGD motifs might contribute to the longtumor retention times of (111)In(DOTA-2P-RGD(4)),( 111)In(DOTA-2P4G-RGD(4)) and (111)In(DOTA-6P-RGD(4)) than that of (111)In(DOTA-3P-RGD(3)) at 72 h p.i. Among the (111)In-labeled cyclic RGD tetramers evaluated in the glioma model, (111)In(DOTA-2P4G-RGD(4)) has very high tumoruptake with the best tumor/kidney and tumor/liver ratios, suggesting that (90)Y(DOTA-2P4G-RGD(4)) and (177)Lu(DOTA-2P4G-RGD(4)) might have the potential for targeted radiotherapy of integrin α(v)β(3)-positive tumors.

http://www.thno.org/v01p0322.htm

PURPOSE:

In vivo imaging of α(v)β(3) has important diagnostic and therapeutic applications. (18)F-Galacto-arginine-glycine-aspartic acid (RGD) has been developed for positron emission tomography (PET) imaging of integrin α(v)β(3) expression and is now being tested on humans. Dimerization and multimerization of cyclic RGD peptides have been reported to improve the integrin α(v)β(3)-binding affinity due to the polyvalency effect. Here, we compared a number of new dimeric RGD peptide tracers with the clinically used (18)F-galacto-RGD.

PROCEDURES:

RGD monomers and dimers were coupled with galacto or PEG(3) linkers, and labeled with (18)F using 4-nitrophenyl 2-(18)F-fluoropropionate ((18)F-NFP) or N-succinimidyl 4-(18)F-fluorobenzoate as a prosthetic group. The newly developed tracers were evaluated by cell-based receptor-binding assay, biodistribution, and small-animal PET studies in a subcutaneous U87MG glioblastoma xenograft model.

RESULTS:

Starting with (18)F-F(-), the total reaction time for (18)F-FP-SRGD2 and (18)F-FP-PRGD2 is about 120 min. The decay-corrected radiochemical yields for (18)F-FP-SRGD2 and (18)F-FP-PRGD2 are 52 ± 9% and 80 ± 7% calculated from (18)F-NFP. Noninvasive small-animal PET and direct tissue sampling experiments demonstrated that the dimeric RGD peptides had significantly higher tumor uptake as compared to (18)F-galacto-RGD.

CONCLUSION:

Dimeric RGD peptide tracers with relatively high tumor integrin-specific accumulation and favorable in vivo kinetics may have the potential to be translated into clinic for integrin α(v)β(3) imaging.

http://dx.doi.org/10.1007/s11307-009-0284-2

Integrin alphavbeta3 plays great roles in tumor angiogenesis, invasion, and metastasis. We report here the noninvasive visualization of tumor integrin alphavbeta3 expression by using near-infrared fluorescence (NIRF) imaging of an IRDye800-labeled new cyclic RGD (arginine-glycine-aspartic acid)dimer with tetra(ethylene glycol) (PEG4) linkers (ie, E[PEG4-c(RGDfK)]2, PEG4 = 15-amino-4,7,10,13-tetraoxapentadecanoic acid) in a U87MG tumor model. Fluorescent dye-labeled E[PEG4-c(RGDfK)]2 were subjected to in vitro cell staining, in vivo NIRF imaging, ex vivo NIRF imaging, and histologic studies. The in vitro and in vivo characterization of dye-labeled E[PEG4-c(RGDfK)]2 were compared with dye-labeled RGD dimer without PEG4 linkers (namely, E[c(RGDfK)]2). Both Cy5.5-E[PEG4-c(RGDfK)]2 and Cy5.5-E[c(RGDfK)]2 exhibited integrin alphavbeta3 binding specificity in a cell-staining experiment. In vivo NIRF imaging showed higher tumor accumulation and tumor to background contrast of IRDye800-E[PEG4-c(RGDfK)]2 over IRDye800-E[c(RGDfK)]2. The tumor integrin alphavbeta3 specificity of IRDye800-E[PEG4-c(RGDfK)]2 was confirmed by successful inhibition of tumor uptake in the presence of an excess dose of c(RGDfK). Histologic examination revealed both tumor vasculature and tumor cellintegrin alphavbeta3 binding of IRDye800-E[PEG4-c(RGDfK)]2 in vivo. In summary, NIRF imaging with IRDye800-E[PEG4-c(RGDfK)]2 offers an easy, fast, and low-cost way to detect and semiquantify tumor integrin alphavbeta3 expression in living subjects.http://dx.doi.org/10.2310/7290.2009.00032

Radioimmunotherapy (RIT) is a promising approach for the treatment of a wide variety of malignancies. The aim of this study was to investigate the therapeutic efficacy of (131)I-labeled anticarcinoembryonic antigen (CEA) monoclonal antibody CL58 in a human colon cancer mouse model. In vitro and in vivo characteristics of (125)I-CL58 were evaluated in LS180 human colon cancer cells and the nude mouse model. (131)I-CL58 was prepared and its in vivo therapeutic efficacy was tested. (125)I-CL58 showed high affinity to LS180 cells, as well as high tumor uptake and long tumor retention in LS180 tumor xenografts. (131)I-CL58 exhibited dose-dependent inhibition of LS180 tumor growth. With the excellent in vitro and in vivo characteristics, and the effective therapy for colon cancer in animal model, (131)I-CL58 is a promising agent for RIT of CEA-positive tumors including colon cancer.

In this study, we reported the preparation and evaluation of (177)Lu-DOTA-RGD2, (177)Lu-DOTA-Bz-RGD2 and (177)Lu-DTPA-Bz-RGD2 (RGD2 = E[c(RGDfK)](2)) as a potential therapeutic radiotracers for the treatment of integrin alpha(v)beta(3)-positive tumors. The BALB/c nude mice bearing the U87MG human glioma xenografts were used to evaluate the biodistribution characteristics and excretion kinetics of (177)Lu-DOTA-RGD2, (177)Lu-DOTA-Bz-RGD2 and (177)Lu-DTPA-Bz-RGD2. It was found that there were no major differences in their lipophilicity and biodistribution characteristics, particularly at latter time points. A major advantage of using DTPA-Bz as the bifunctional chelator (BFC) was its high radiolabeling efficiency (fast and high yield radiolabeling) at room temperature. Using DOTA and DOTA-Bz as BFCs, the radiolabeling kinetics was slow, and heating at 100 degrees C and higher DOTA-conjugate concentration were needed for successful (177)Lu-labeling. Therefore, DTPA-Bz is an optimal BFC for routine preparationof (177)Lu-labeled cyclic RGDfK peptides, and (177)Lu-DTPA-Bz-RGD2 is worthy of further investigation for targeted radiotherapy of integrin alpha(v)beta(3)-positive tumors.

This report presents the synthesis and evaluation of (111)In(DOTA-6G-RGD(4)) (DOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetracetic acid; 6G-RGD(4) = E{G(3)-E[G(3)-c(RGDfK)](2)}(2) and G(3) = Gly-Gly-Gly), (111)In(DOTA-RGD(4)) (RGD(4) = E{E[c(RGDfK)](2)}(2)) and (111)In(DOTA-3G-RGD(2)) (3G-RGD(2) = G(3)-E[G(3)-c(RGDfK)](2)) as new radiotracers for imaging integrin alpha(v)beta(3)-positive tumors. The IC(50) values of DOTA-6G-RGD(4), DOTA-RGD(4), and DOTA-3G-RGD(2) were determined to be 0.4 +/- 0.1, 1.4 +/- 0.1 and 1.1 +/- 0.1 nM against (125)I-c(RGDyK) bound to integrin alpha(v)beta(3)-positive U87MG human glioma cells. (111)In(DOTA-6G-RGD(4)), (111)In(DOTA-RGD(4)), and (111)In(DOTA-3G-RGD(2)) were prepared by reacting (111)InCl(3) with the respective DOTA conjugate in NH(4)OAc buffer (100 mM, pH = 5.5). Radiolabeling could be completed by heating the reaction mixture at 100 degrees C for 15-20 min. The specific activity was approximately 1850 MBq/micromol for (111)In(DOTA-3G-RGD(2)) and approximately 1480 MBq/micromol for (111)In(DOTA-6G-RGD(4)). The athymic nude mice bearing U87MG human glioma xenografts were used to evaluate tumor uptake and excretion kinetics of (111)In(DOTA-6G-RGD(4)), (111)In(DOTA-RGD(4)), and (111)In(DOTA-3G-RGD(2)). The results from both the integrin alpha(v)beta(3) binding assay and biodistribution studies suggest that the tetrameric cyclic RGD peptides, such as RGD(4) and 6G-RGD(4), are most likely bivalent in binding to the integrin alpha(v)beta(3). Both (111)In(DOTA-6G-RGD(4)) and (111)In(DOTA-RGD(4)) had significantly higher tumor uptake than (111)In(DOTA-3G-RGD(2)) at 24-72 h postinjection due to the extra RGD motifs in RGD(4) and 6G-RGD(4). (111)In(DOTA-3G-RGD(2)) had very little metabolism, while (111)In(DOTA-6G-RGD(4)) had significant metabolism during its excretion via both renal and hepatobiliary routes over the 2 h period, probably due to its much larger size. The combination of high tumor uptake with long tumor retention suggests that their corresponding (90)Y and (177)Lu analogues M(DOTA-6G-RGD(4)) (M = (90)Y and (177)Lu) might be useful as therapeutic radiotracers for treatment of integrin alpha(v)beta(3)-positive solid tumors.

Panitumumab (ABX-EGF or Vectibix), the first fully human monoclonal antibody targeting epidermal growth factor receptor (EGFR), was approved by the Food and Drug Administration for treatment of patients with metastatic colorectal cancer. Here, we report for the first time the radioimmunotherapy(RIT) of EGFR-positive human head and neck cancer in a nude mouse model using pure beta(-) emitter (90)Y-labeled panitumumab. Biodistribution and planar gamma-imaging studies were carried out with (111)In-DOTA-panitumumab. The RIT efficacy of (90)Y-DOTA-panitumumab was evaluated in UM-SCC-22B tumor model. CD31, Ki67, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling, and H&E staining were done on UM-SCC-22B tumor sections after treatment. The tumor uptake of (111)In-DOTA-panitumumab in UM-SCC-22B tumor-bearing nude mice was 26.10 +/- 4.93, 59.11 +/- 7.22, 44.57 +/- 9.80, 40.38 +/- 7.76, and 14.86 +/- 7.23 % injected dose per gram of tissue at 4, 24, 72, 120, and 168 hours after injection, respectively. Immunotherapy with cold panitumumab (four doses of 10 mg/kg) did not cause significant antitumor effect. RIT with a single dose of 100 microCi (90)Y-DOTA-panitumumab caused significant tumor growth delay and improved the survival in UM-SCC-22B tumor model. A single dose of 200 microCi (90)Y-DOTA-panitumumab led to almost complete tumor regression (tumor volumes were 34.83 +/- 11.11 mm(3) and 56.02 +/- 39.95 mm(3) on days 0 and 46 after treatment, respectively). Histopathologic analysis of tumors and normal organs further validated the therapeutic efficacy and limited systemic toxicity of (90)Y-DOTA-panitumumab. The high tumor uptake and prolonged tumor retention, as well as effective therapy, reveal that (90)Y-DOTA-panitumumab may be a promising radioimmunotherapeutic agent to treat EGFR-positive solid tumors.

(c) 2010 AACR.

http://dx.doi.org/10.1158/1535-7163.MCT-10-0444

Molecular imaging provides a powerful tool for early disease detection, characterization, and real-time monitoring of therapeutic responses. Central to molecular imaging is the development of imaging probes. Receptors that are overexpressed in tumors have been potential targets for cancer imaging using targeted molecular probes. Since many cancer types simultaneously overexpress several receptors, the design of dual receptor-targeted molecular imaging probes has recently been proposed. Peptide heterodimers, and microbubble-based dual-targeted probes have shown especially good performance for in vivo cancer imaging. The success of these molecular probes demonstrates that the dual-targeting strategy is generally a good approach for developing molecular probes. In this review, we will introduce the current state of development of dual-targeted molecular imaging probes and summarize the various dual-targeted molecular probes for in vivo cancer imaging.

http://www.benthamdirect.org/pages/b_viewarticle.p

PURPOSE:

This report presents the synthesis of a cyclic RGD dimer conjugate, MAG(2)-G(3)-E[G(3)-c(RGDfK)](2) (MAG(2)-3G(3)-dimer, G(3) = Gly-Gly-Gly, MAG(2) = S-benzoyl mercaptoacetylglycylglycyl), and evaluation of its (99m)Tc complex, (99m)TcO(MAG(2)-3G(3)-dimer), as a new radiotracer for imaging the tumor integrin alpha(v)beta(3) expression.

METHODS:

An in vitro displacement assay was used to determine the integrin alpha(v)beta(3) binding affinity of MAG(2)-3G(3)-dimer against (125)I-c(RGDyK) bound to U87MG human glioma cells. The athymic nude mice bearing U87MG glioma xenografts were used for biodistribution and planar imaging studies.

RESULTS:

We found that (1) MAG(2) is such a highly effective bifunctional chelator that (99m)TcO(MAG(2)-3G(3)-dimer) can be prepared in high yield (radiochemical purity >95%) and with high specific activity ( approximately 5 Ci/micromol) using a kit formulation; (2) (99m)TcO(MAG(2)-3G(3)-dimer) has very high solution stability in the kit matrix; and (3) (99m)TcO(MAG(2)-3G(3)-dimer) has very fast clearance kinetics from the intestine, liver, and kidneys. Among the (99m)Tc-labeled cyclic RGD peptides evaluated in the xenografted U87MG glioma models, (99m)TcO(MAG(2)-3G(3)-dimer) has the best pharmacokinetics and tumor to background ratios (tumor/liver = 4.29 +/- 1.00 at 30 min postinjection and 8.29 +/- 1.50 at 120 min postinjection; tumor/kidney = 1.16 +/- 0.19 at 30 min postinjection and 2.49 +/- 0.25 at 120 min postinjection). Planar imaging studies showed that tumors in the glioma-bearing mice administered with (99m)TcO(MAG(2)-3G(3)-dimer) can be visualized with excellent contrast as early as 15 min postinjection. (99m)TcO(MAG(2)-3G(3)-dimer) was able to maintain its chemical integrity in kidneys (>80% intact) and liver (>95% intact) over the 2-h period. However, there was significant metabolism (>50% of the injected radioactivity) detected in both urine and feces samples.

CONCLUSION:

(99m)TcO(MAG(2)-3G(3)-dimer) is a very attractive radiotracer for early detection of integrin alpha(v)beta(3)-positive tumors and has significant advantages over the (18)F-labeled RGD peptide radiotracers with respect to the cost, availability, and easiness for routine clinical preparation.

Radiolabeled RGD (Arg-Gly-Asp) and bombesin (BBN) radiotracers that specifically target integrin alpha(v)beta(3) and gastrin releasing peptide receptor (GRPR) are both promising radiopharmaceuticals for tumor imaging. We recently designed and synthesized a RGD-BBN heterodimeric peptide with both RGD and BBN motifs in one single molecule. The (18)F-labeled RGD-BBN heterodimer exhibited dual integrin alpha(v)beta(3) and GRPR targeting in a PC-3 prostate cancer model. In this study we investigated whether radiolabeled RGD-BBN tracers can be used to detect breast cancer by using microPET. Cell binding assay demonstrated that the high GRPR expressing breast cancer cells typically express low to moderate level of integrin alpha(v)beta(3), while high integrin alpha(v)beta(3) expressing breast cancer cells have negligible level of GRPR. We labeled RGD-BBN heterodimer with three positron emitting radionuclides (18)F, (64)Cu, and (68)Ga and investigated the corresponding PET radiotracers in both orthotopic T47D (GRPR(+)/low integrin alpha(v)beta(3)) and MDA-MB-435 (GRPR(-)/integrin alpha(v)beta(3)(+)) breast cancer models. The three radiotracers all possessed in vitro dual integrin alpha(v)beta(3) and GRPR binding affinity. The advantages of the RGD-BBN radiotracers over the corresponding BBN analogues are obvious for imaging MDA-MB-435 (GRPR(-)/integrin alpha(v)beta(3)(+)) tumor. (18)F-FB-PEG(3)-RGD-BBN showed lower tumor uptake than (64)Cu-NOTA-RGD-BBN and (68)Ga-NOTA-RGD-BBN but was able to visualize breast cancer tumors with high contrast. Synthesis of (64)Cu-NOTA-RGD-BBN and (68)Ga-NOTA-RGD-BBN is much faster and easier than (18)F-FB-PEG(3)-RGD-BBN. (64)Cu-NOTA-RGD-BBN showed prolonged tumor uptake but also higher liver retention and kidney uptake than (68)Ga-NOTA-RGD-BBN and (18)F-FB-PEG(3)-RGD-BBN. (68)Ga-NOTA-RGD-BBN possessed high tumor signals but also relatively high background uptake compared with the other two radiotracers. In summary, the prosthetic labeling groups, chelators, and isotopes all have a profound effect on the tumor targeting efficacy and in vivo kinetics of the RGD-BBN tracers for dual integrin and GRPR recognition. Further development of suitably labeled RGD-BBN tracers for PET imaging of cancer is warranted.

PURPOSE:

Various radiolabeled Arg-Gly-Asp (RGD) peptides have been previously investigated for tumor integrin alpha(v)beta(3) imaging. To further develop RGD radiotracers with enhanced tumor-targeting efficacy and improved in vivo pharmacokinetics, we designed a new RGD homodimeric peptide with two PEG(4) spacers (PEG(4) = 15-amino-4,7,10,13-tetraoxapentadecanoic acid) between the two monomeric RGD motifs and one PEG(4) linker on the glutamate alpha-amino group ((18)F-labeled PEG(4)-E[PEG(4)-c(RGDfK)](2), P-PRGD2), as a promising agent for noninvasive imaging of integrin expression in mouse models.

METHODS:

P-PRGD2 was labeled with (18)F via 4-nitrophenyl 2-(18)F-fluoropropionate ((18)F-FP) prosthetic group. In vitro and in vivo characteristics of the new dimeric RGD peptide tracer (18)F-FP-P-PRGD2 were investigated and compared with those of (18)F-FP-P-RGD2 ((18)F-labeled RGD dimer without two PEG(4) spacers between the two RGD motifs). The ability of (18)F-FP-P-PRGD2 to image tumor vascular integrin expression was evaluated in a 4T1 murine breast tumor model.

RESULTS:

With the insertion of two PEG(4) spacers between the two RGD motifs, (18)F-FP-P-PRGD2 showed enhanced integrin alpha(v)beta(3)-binding affinity, increased tumor uptake and tumor-to-nontumor background ratios compared with (18)F-FP-P-RGD2 in U87MG tumors. MicroPET imaging with (18)F-FP-P-PRGD2 revealed high tumor contrast and low background in tumor-bearing nude mice. Biodistribution studies confirmed the in vivo integrin alpha(v)beta(3)-binding specificity of (18)F-FP-P-RGD2. (18)F-FP-P-PRGD2 can specifically image integrin alpha(v)beta(3) on the activated endothelial cells of tumor neovasculature.

CONCLUSION:

(18)F-FP-P-PRGD2 can provide important information on integrin expression on the tumor vasculature. The high integrin binding affinity and specificity, excellent pharmacokinetic properties and metabolic stability make the new RGD dimeric tracer (18)F-FP-P-PRGD2 a promising agent for PET imaging of tumor angiogenesis and for monitoring the efficacy of antiangiogenic treatment.

Radiolabeled RGD and bombesin peptides have been extensively investigated for tumor integrin alpha(v)beta(3) and GRPR imaging, respectively. Due to the fact that many tumors are both integrin and GRPR positive, we designed and synthesized a heterodimeric peptide Glu-RGD-BBN, which is expected to be advantageous over the monomeric peptides for dual-receptor targeting. A PEG(3) spacer was attached to the glutamate alpha-amino group of Glu-RGD-BBN to enhance the (18)F labeling yield and to improve the in vivo kinetics. PEG(3)-Glu-RGD-BBN possesses the comparable GRPR and integrin alpha(v)beta(3) receptor-binding affinities as the corresponding monomers, respectively. The dual-receptor targeting properties of (18)F-FB-PEG(3)-Glu-RGD-BBN were observed in PC-3 tumor model. (18)F-FB-PEG(3)-Glu-RGD-BBN with high tumor contrast and favorable pharmacokinetics is a promising PET tracer for dual integrin and GRPR positive tumor imaging. This heterodimer strategy may also be an applicable method to develop other molecules with improved in vitro and in vivo characterizations for tumor diagnosis and therapy.

PURPOSE:

Radiolabeled cyclic RGD (Arg-Gly-Asp) peptides have great potential for the early tumor detection and noninvasive monitoring of tumor metastasis and therapeutic response. (18)F-labeled RGD analogs ([(18)F]-AH111585 and [(18)F]Galacto-RGD) have been investigated in clinical trials for positron emission tomography (PET) imaging of integrin expression in cancer patients. To develop new RGD radiotracers with higher tumor accumulation, improved in vivo kinetics, easy availability and low cost, we developed two new RGD peptides and labeled them with generator-eluted (68)Ga (t(1/2) = 68 min) for PET imaging of integrin alpha(v)beta(3) expression in tumor xenograft models.

MATERIALS AND METHODS:

The two new cyclic RGD dimers, E[PEG(4)-c(RGDfK)](2) (P(4)-RGD2, PEG(4) = 15-amino-4,7,10,13-tetraoxapentadecanoic acid) and E[Gly(3)-c(RGDfK)](2) (G(3)-RGD2, G(3) = Gly-Gly-Gly) were designed, synthesized and conjugated with 1,4,7-triazacyclononanetriacetic acid (NOTA) for (68)Ga labeling. The microPET imaging and biodistribution of the (68)Ga labeled RGD tracers were investigated in integrin alpha(v)beta(3)-positive tumor xenografts.

RESULTS:

The new RGD dimers with the Gly(3) and PEG(4) linkers showed higher integrin alpha(v)beta(3) binding affinity than no-linker RGD dimer (RGD2). NOTA-G(3)-RGD2 and NOTA-P(4)-RGD2 could be labeled with (68)Ga within 30 min with higher purity (>98%) and specific activity (8.88-11.84 MBq/nmol). Both (68)Ga-NOTA-P(4)-RGD2 and (68)Ga-NOTA-G(3)-RGD2 exhibited significantly higher tumor uptake and tumor-to-normal tissue ratios than (68)Ga-NOTA-RGD2.

CONCLUSION:

Because of their high affinity, high specificity and excellent pharmacokinetic properties, further investigation of the two novel RGD dimers for clinical PET imaging of integrin alpha(v)beta(3) expression in cancer patients is warranted.

http://dx.doi.org/10.1007/s00259-008-1045-1

A novel dual-modality molecular probe composed of biocompatible Fe(3)O(4) nanocrystal, monoclonal antibody and radionuclide was designed and prepared. All functional components in the dual-modality molecular probe, i.e., Fe(3)O(4), PEG, mAb 3H11 and (125)I, were chemically bonded together for forming a stable molecular probe. Systematic in vitro experiments were carried out for evaluating the biological activity of the antibody in the targeting probe. A series of in vivo experiments were performed based on the dual-modality imaging probe for detecting xenografted tumors in nude mice by MRI and gamma-imaging techniques. The pharmacokinetics of the dual-modality molecular probe in tumor-bearing nude mice was studied.

PURPOSE:

Internalization is one of the key steps for anticancer immunoconjugates to deliver the drugs inside of cancer cells. Herein, the internalization property of antiepidermal growth factor receptor (EGFR) monoclonal antibody (mAb) LA22 was evaluated.

MATERIALS AND METHODS:

The binding and internalization properties of LA22 on A549 cells were investigated by using 125I-LA22. In vitro internalization was also confirmed by indirect fluorescent staining. In vivo tumor targeting and internalization of 125I-LA22 were evaluated in the A549 nude mice model.

RESULTS:

The mAb LA22 showed a high affinity to EGFRs expressed on A549 cells (Kd = 0.69 +/- 0.13 nM). The in vitro internalization of LA22 was time- and temperature dependent. The cell-surface-bound LA22 was rapidly internalized at 37 degrees C. The experimental results of LA22 internalization obtained from radioassay and fluorescent staining were consistent with a good linear correlation. At 72 hours postinjection, a clear gamma-image of tumor was obtain in A549 tumor xenografts, and the tumor uptake of 125I-LA22 was 8.00 +/- 0.61 percent injected dose per gram (%ID/g) (2.19 +/- 0.37 %ID/g for 125I-mIgG). Similar to the in vitro observation, 64.06% of the cell-bound mAb LA22 was internalized into the tumor cells in vivo.

CONCLUSIONS:

The mAb, LA22, is a rapid, high-internalizing antibody, and this property makes it a promising vehicle for tumor-targeted drug delivery.

Anti-angiogenesis is a promising strategy for the treatment of cancer. Integrins, consisting of two noncovalently bound transmembrane alpha and beta subunits, are an important molecular family involved in tumor angiogenesis. The blockade of integrin signaling has been demonstrated to be efficient to inhibit tumor growth, angiogenesis, and metastasis. Among all the integrins, alpha(v)beta(3) seems to be the most important one during tumor angiogenesis. The inhibition of integrin alpha(v)beta(3) signaling with antibodies, peptides, peptidomimetics, and other antagonists has great potential in the treatment of cancer. In addition, integrin alpha(v)beta(3) is highly expressed on activated endothelial cells, new-born vessels as well as some tumor cells, but is not present in resting endothelial cells and most normal organ systems, making it a suitable target for anti-angiogenic therapy. In this article we will review the role of integrin alpha(v)beta(3) in angiogenesis, present recent progress in the use of integrin alpha(v)beta(3) antagonists and integrin-targeted delivery systems as potential cancer therapeutics, and discuss future perspectives.

http://dx.doi.org/10.1002/ddr.20265

Abstract

In this report, we present in vitro and in vivo evaluation of three 111 In-labeled DTPA conjugates of a cyclic RGDfK dimer: DTPA-Bn-SU016 (SU016 = E[c(RGDfK)] 2; DTPA-Bn = 2-( p-isothioureidobenzyl)diethylenetriaminepentaacetic acid), DTPA-Bn-E-SU016 ( E = glutamic acid) and DTPA-Bn-Cys-SU016 (Cys = cysteic acid). The integrin alpha vbeta 3 binding affinities of SU016, DTPA-Bn-SU016, DTPA-Bn-E-SU016, and DTPA-Bn-Cys-SU016 were determined to be 5.0 +/- 0.7 nM, 7.9 +/- 0.6 nM, 5.8 +/- 0.6 nM, and 6.9 +/- 0.9 nM, respectively, against 125 I-c(RGDyK) in binding to integrin alpha vbeta3, suggesting that E or Cys residue has little effect on the integrin alpha vbeta3 affinity of E[c(RGDfK)] 2. It was also found that the 111 In-labeling efficiency of DTPA-Bn-SU016 and DTPA-Bn-E-SU016 is 3-5 times better than that of DOTA analogues due to fast chelation kinetics and high-yield 111 In-labeling under mild conditions (e.g., room temperature). Biodistribution studies were performed using BALB/c nude mice bearing U87MG human glioma xenografts. 111 In-DTPA-Bn-SU016, 111 In-DTPA-Bn-E-SU016, and 111 In-DTPA-Bn-Cys-SU016 all displayed rapid blood clearance. Their tumor uptake was comparable between 0.5 and 4 h postinjection (p.i.) within experimental error. 111 In-DTPA-Bn-E-SU016 had a significantly lower ( p < 0.01) kidney uptake than 111 In-DTPA-Bn-SU016 and 111 In-DTPA-Bn-Cys-SU016. The liver uptake of 111 In-DTPA-Bn-SU016 was 1.69 +/- 0.18% ID/g at 24 h p.i., while the liver uptake values of 111 In-DTPA-Bn-E-SU016 and 111 In-DTPA-Bn-Cys-SU016 were 0.55 +/- 0.11% ID/g and 0.79 +/- 0.15% ID/g at 24 h p.i., respectively. Among the three 111 In radiotracers evaluated in this study, 111 In-DTPA-Bn-E-SU016 has the lowest liver and kidney uptake and the best tumor/liver and tumor/kidney ratios. Results from metabolism studies indicated that there is little metabolism (<10%) for three 111 In radiotracers at 1 h p.i. Imaging data showed that tumors can be clearly visualized at 4 h p.i. with good contrast in the tumor-bearing mice administered with 111 In-DTPA-Bn-E-SU016. It is concluded that using a glutamic acid linker can significantly improve excretion kinetics of the 111 In-labeled E[c(RGDfK)] 2 from liver and kidneys.

http://dx.doi.org/10.1021/bc7002988