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Thomas M Behr

Publications and source records attributed to Thomas M Behr.

31 records · Page 2Linked to original sources
PubMed2003

Imaging lung tumors with peptide-based radioligands.

The somatostatin analogue octreotide was the first radiopeptide to be used for the scintigraphic diagnosis of tumors. Somatostatin receptor scintigraphy (SRS) has proven its value, especially in the detection of gut neuroendocrine tumors. In some tumor types, it is considered the diagnostic gold standard. In carcinoid tumors of the lung, SRS is of major importance in diagnostic workup. Furthermore, the combination of computed tomography scanning and SRS is a reliable and cost-effective approach for the evaluation of single pulmonary nodules. Despite these favorable properties, SRS fails in the detection of metastases of lung cancer. The problem of false-positive results in SRS resulting from inflammatory disease might be overcome by the use of new radiopeptides such as cholecystokinin-B receptor-binding gastrin analogues. This article focuses on the current status of peptide-receptor scintigraphy in the diagnosis of lung tumors and on future developments in this field.

Cost-Benefit Analysis↗
PubMed2003

p38 mitogen-activated protein kinase inhibitors for the treatment of chronic cardiovascular disease.

p38 Mitogen-activated protein kinase (MAPK) has been implicated in cardiovascular disease and is activated by various factors, including neurohormones (e.g., catecholamines, angiotensin II and endothelin), hypoxia and wall stress. Activation of p38 MAPK can cause cardiac hypertrophy, negative inotropy and endothelial dysfunction. All of these conditions lead to chronic cardiovascular disease, which is becoming an ever growing burden on society. p38 MAPK inhibition may therefore be an interesting therapeutic approach to the treatment of various cardiovascular diseases. However, in vitro and in vivo results are conflicting and caution must be applied in the translation of bench results to the clinic.

Animals↗
PubMed2002

Use of the incretin hormone glucagon-like peptide-1 (GLP-1) for the detection of insulinomas: initial experimental results.

The non-invasive detection of insulinomas remains a diagnostic problem that is not solved by means of somatostatin receptor scintigraphy. We investigated the biokinetics and specificity of uptake and degradation of the incretin hormone glucagon-like peptide-1 (GLP-1) in a rat insulinoma cell line (RINm5F) in order to ascertain whether radiolabelled GLP-1 may be suitable for specific visualisation of insulinomas in vivo. GLP-1 (7-36)amide was radioiodinated according to the iodogen method. The specificity of the uptake of [(125)I]GLP-1(7-36)amide by RINm5F cells was investigated. Degradation products of GLP-1 (7-36)amide in the cell medium were purified by HPLC. Their masses and amino acid sequences were determined by (252)Cf-plasma desorption mass spectrometry. Lysosomal degradation was inhibited and after differential centrifugation the amount of radiotracer incorporated into lysosomes was determined. Biodistribution studies were performed in a rat insulinoma model (NEDH rats and RINm5F cells) with [(123)I]GLP-1(7-36)amide and its more stable agonist [(123)I]exendin 3. The uptake of radiotracer into insulinoma cells reached a maximum within 5 min. It was inhibited by an excess of unlabelled peptide. [(125)I]GLP-1(7-36)amide accumulated in the cells if lysosomal degradation was inhibited. Degradation products of the peptide were found in the cell medium. We determined their mass and derived their amino acid sequence. Radiolabelling of exendin 3 was more difficult than that of GLP-1 because of the lack of tyrosine in its primary structure. Biodistribution studies showed rapid blood clearance and uptake of the radiotracer into the tumour and the pancreas. It was also possible to detect insulinomas in an animal model by external scintigraphy using radioiodinated GLP-1 (7-36)amide and exendin 3. GLP-1 (7-36)amide is specifically internalised into insulinoma cells by a receptor-mediated mechanism. Our results demonstrate that GLP-1 receptor-directed scintigraphy may be a new method for the detection of insulinomas in vivo. Due to the short half-life of GLP-1, its more stable analogue exendin 3 may better suit this purpose in vivo.

Animals↗
PubMed2002

High-dose myeloablative radioimmunotherapy of mantle cell non-Hodgkin lymphoma with the iodine-131-labeled chimeric anti-CD20 antibody C2B8 and autologous stem cell support. Results of a pilot study.

BACKGROUND: CD20 has been used successfully as a target molecule for conventional low-dose, as well as high-dose, myeloablative radioimmunotherapy (RIT) of B-cell non-Hodgkin lymphoma (NHL). Mantle cell lymphoma (MCL) is an especially aggressive, prognostically unfavorable subtype of B-cell NHL, associated with an overall 5-year survival rate of less than 20%. Recent evidence has failed to show convincing therapeutic efficacy of conventional, nonmyeloablative RIT in patients with MCL. The aim of this pilot study was to investigate whether high-dose, myeloablative RIT with the iodine-131 ((131)I)-labeled chimeric anti-CD20 antibody C2B8 (rituximab, obtained as Mabthera from Roche Pharma, Reinach, Switzerland) is therapeutically effective in MCL patients. METHODS: A total of seven patients with chemorefractory or relapsed MCL were studied in this pilot trial. All had relapsed after high-dose chemotherapy with autologous stem cell transplantation (four of them combined with 12 grays (Gy) total-body irradiation). A diagnostic-dosimetric study was performed with approximately 10 mCi of (131)I-labeled C2B8 at a protein dose of 2.5 mg per kg body weight, in order to assess its biodistribution and dosimetry. If splenic pooling was observed, as is typically the case in patients with splenomegaly, the protein dose was doubled in additional studies until a "favorable" biodistribution was obtained. Therapy was performed with myeloablative doses of 261-495 mCi of (131)I-labeled C2B8 at the previously optimized protein dose, aiming at lung doses less-than-or-equal 27 Gy. Homologous stem cell support was provided. Clinical follow-up was obtained at 3-month intervals for up to 38 months (median observation time, 25 months). Overall, in six patients the 2.5 mg/kg protein dose was used, whereas in one patient with splenomegaly, 10 mg/kg was necessary to overcome the splenic antigenic sink. RESULTS: Blood cell nadirs were reached at 2-3 weeks after therapy infusion, but all patients reengrafted at 7-10 days after stem cell reinfusion. Nonhematologic toxicity was restricted to mild-to-moderate nausea, fever, transient bilirubin, or liver enzyme elevations. One patient with preexisting alcoholic cirrhosis experienced a deterioration of liver function. Despite thyroid blocking, 5 of 7 patients developed hypothyroidism, requiring thyroxine substitution at 6-18 months after RIT. Six patients experienced a complete and one a good partial remission. Five patients were still in CR at the time this article was written, and six are still alive for more than 3 years; one patient relapsed locally at 3 months and one systemically at 26 months after RIT. CONCLUSIONS: High-dose myeloablative radioimmunotherapy with (131)I-labeled anti-CD20 antibodies seems to be associated with a high response rate and moderate toxicity in patients with MCL. Further follow-up to monitor the long-term outcome as well as systematic prospective clinical studies are indicated.

Adult↗
PubMed2002

Radioimmunotherapy of small-volume disease of metastatic colorectal cancer.

BACKGROUND: Whereas radioimmunotherapy (RIT) has shown disappointing results in bulky, solid tumors, preclinical results in small-volume disease and in an adjuvant setting are promising. In a previous Phase I study, the authors had encouraging results with the iodine-131 ((131)I)-labeled humanized anti-carcinoembryonic antigen (anti-CEA) antibody (MAb) hMN-14 in small-volume disease of colorectal cancer. The aim of this study was to evaluate, in a subsequent Phase II trial, the therapeutic efficacy of this (131)I-labeled humanized anti-CEA antibody in colorectal cancer patients with small-volume disease or in an adjuvant setting. METHODS: Thirty colorectal cancer patients, with small-volume metastatic disease (n = 21; all lesions less-than-or-equal 3.0 cm, and chemorefractory to 5-fluorouracil and folinic acid) or in an adjuvant setting (n = 9), 4-6 weeks after surgical resection of liver metastases with curative intention, were studied. The patients were given a single injection of (131)I-hMN-14 immunoglobulin G at a 60 mCi/m(2) dose level, which was shown to be the maximum tolerated dose in the previous Phase I study. Follow-up was obtained at 3-month intervals for as long as 36 months. RESULTS: At a mean blood-based red marrow dose of 1.8 +/- 0.8 Gy, myelotoxicity was the only toxicity observed, but only 1 of 28 assessable patients developed transient Grade 4 thrombocytopenia. Of the 21 patients with radiologically documented lesions, 19 were assessable. Three experienced partial remission and eight showed minor responses up to 15 months in duration (corresponding to an objective response rate of 16% and an overall response rate of 58%; the mean duration of response was 9 months). At the time this article was written, seven of nine patients in the adjuvant setting had remained free of disease for up to 36 months (one patient relapsed after 6 months and another after 30 months), whereas the relapse rate in a historical control group receiving chemotherapy was 67% over the same time period. Five patients with radiologically documented lesions, having experienced at least disease stabilization as a consequence of RIT, were retreated at the same 60-mCi/m(2) dose level at 8-16 months after the first therapy. No evidence of increased toxicity was observed (no hematologic toxicity was higher than Grade 3). Two of four assessable retreated patients experienced partial remissions; one of these four again experienced disease stabilization as a consequence of the second radioantibody therapy injection. CONCLUSIONS: These data suggest that RIT is a safe and effective form of therapy for small-volume colorectal cancer and has potential as treatment for colorectal cancer in an adjuvant setting. Toxicity is restricted to mild and transient leuko- and thrombocytopenia. Retreatment seems to be a feasible option. A prospective randomized comparison with standard chemotherapy is indicated.

Antibodies, Monoclonal↗
PubMed2002

Cholecystokinin-B (CCK-B)/gastrin receptor targeting peptides for staging and therapy of medullary thyroid cancer and other CCK-B receptor expressing malignancies.

Nuclear medicine is engaged with the detection of pathological processes with the help of radionuclides. An interesting approach is to target antigens, symporters, or receptors with diagnostic and therapeutic radionuclides. Different peptide receptors like somatostatin, bombesin/GRP or VIP are (over)expressed on cancer cells, and are therefore an ideal target for the diagnosis and therapy in nuclear medicine with radiolabeled peptides. The somatostatin analogue OctreoScan [octreotide coupled with diethylene-triamine-pentaacetate (DTPA)] can be labeled with In-111 and is widely used in nuclear oncology for the staging of different tumors (e.g., carcinoids). Other peptides like neurotensin, bombesin/GRP, and VIP are under (pre)clinical investigations. The staging of metastatic medullary thyroid cancer (MTC) with the conventional radiological procedures is sometimes difficult. The high sensitivity of the pentagastrin stimulation test in detecting primary or metastatic MTC indicates the presence of tumor, but its localization is often not possible. This reaction of the tumor cells to the pentagastrin stimulation test suggests a widespread expression of the corresponding receptor type on human MTC. Indeed, autoradiographic studies demonstrated cholecystokinin (CCK)-B/gastrin receptors not only in over 90% of MTCs, but in a high percentage of small cell lung cancers, stromal ovarian, and potentially a variety of other tumors, including gastrointestinal adenocarcinomas, neuroendocrine tumors, and malignant glioma. The aim of our recent work was to develop and systematically optimize suitable radioligands for targeting CCK-B receptors in vivo and to investigate their role in the staging and therapy of MTC and other CCK-B receptor expressing malignancies. For this purpose, a variety of CCK/gastrin-related peptides, all having in common the C-terminal CCK receptor binding tetrapeptide sequence -Trp-Met-Asp-PheNH(2) or derivatives thereof, were investigated. They were members of the gastrin- or cholecystokinin families, or possessed characteristics of both, which differ by the intramolecular position of a tyrosyl moiety. Their stability and affinity were studied and optimized in vitro and in vivo; their biodistribution and therapeutic efficacy were tested in preclinical models. Best tumor uptake and tumor-to-nontumor ratios were obtained with members of the gastrin family, due to their superior selectivity and affinity for the CCK-B receptor subtype. Radiometal-labeled derivatives of minigastrin showed excellent targeting of CCK-B receptor expressing tissues in animals and healthy human volunteers. Preclinical therapy experiments in MTC-bearing animals showed significant antitumor efficacy. In a subsequent clinical study, 75 MTC patients with metastatic MTC were investigated; 43 suffered of known, 32 of occult disease. CCK-B receptor scintigraphy was performed with (111)In-DTPA-D-Glu(1)-minigastrin. The normal organ uptake was essentially confined to the stomach (and to a lower extent, to the gallbladder and, in premenopausal women, to normal breast tissue) as a result of CCK-B receptor specific binding, and to the kidneys as excretory organs. All tumor manifestations known from conventional imaging were visualized as early as 1 h p.i., with increasing tumor-to-background ratios over time; at least one lesion was detected in 29/32 patients with occult disease (patient-based sensitivity 91%). Among them were local recurrences, lymph node, pulmonary, hepatic, splenic, and bone (marrow) metastases. Eight patients with advanced metastatic disease were injected in a dose-escalation study with potentially therapeutic activities of a (90)Y-labeled minigastrin derivative at 4-6-weekly intervals (30-50 mCi/m(2) per injection for a maximum of four injections). Hematologic and renal were identified as the dose-limiting toxicities at the 40 and 50 mCi/m(2) levels. Two patients experienced partial remissions, 4 stabilization of their previously rapidly progressing disease. These data suggest that CCK-B receptor ligands may be a useful new class of receptor binding peptides for diagnosis and therapy of a variety of (CCK-B receptor expressing) tumor types. They allow for a sensitive and reliable staging of patients with metastatic MTC. Initial therapeutic results are promising, but nephrotoxicity is a major concern to be solved.

Animals↗
PubMed2002

Cholecystokinin-B/Gastrin receptor-targeting peptides for staging and therapy of medullary thyroid cancer and other cholecystokinin-B receptor-expressing malignancies.

The high sensitivity of the pentagastrin stimulation test in detecting primary or metastatic medullary thyroid cancer (MTC) suggests a widespread expression of the corresponding receptor type on human MTC. Indeed, autoradiographic studies demonstrated cholecystokinin (CCK)-B/gastrin receptors not only in more than 90% of MTCs, but also in a high percentage of small-cell lung cancers, stromal ovarian tumors, and potentially a variety of other tumors, including gastrointestinal adenocarcinomas, neuroendocrine tumors, and malignant glioma. The aim of our work was to develop and systematically optimize suitable radioligands for targeting CCK-B receptors in vivo and to investigate their role in the staging and therapy of MTC and other CCK-B receptor expressing malignancies. For this purpose, a variety of CCK/gastrin-related peptides, all having in common the C-terminal CCK-receptor binding tetrapeptide sequence-Trp-Met-Asp-PheNH(2) or derivatives thereof, were investigated. They were members of the gastrin or cholecystokinin families or possessed characteristics of both, which differ by the intramolecular position of a tyrosyl moiety. Their stability and affinity were studied and optimized in vitro and in vivo; their biodistribution and therapeutic efficacy were tested in preclinical models. Best tumor uptake and tumor to nontumor ratios were obtained with members of the gastrin family, because of their superior selectivity and affinity for the CCK-B receptor subtype. Radiometal-labeled derivates of minigastrin showed excellent targeting of CCK-B receptor expressing tissues in animals and healthy human volunteers. Preclinical therapy experiments in MTC-bearing animals showed significant antitumor efficacy. In a subsequent clinical study, 45 MTC patients with metastatic MTC were investigated; 23 had known and 22 had occult disease. CCK-B receptor scintigraphy was performed with (111)In-diethylenetriamine pentaacetic acid-d-Glu(1)-minigastrin. The normal organ uptake was essentially confined to the stomach (and, to a lesser extent, to the gallbladder and, in premenopausal women, to normal breast tissue) as a result of CCK-B receptor specific binding and to the kidneys, as excretory organs. All tumor manifestations known from conventional imaging were visualized as early as 1 hour postinjection, with increasing tumor to background ratios over time; at least 1 lesion was detected in 20 of 22 patients with occult disease (patient-based sensitivity, 91%). Among them were local recurrences and lymph node, pulmonary, hepatic, splenic, and bone (marrow) metastases. Eight patients with advanced metastatic disease were injected in a dose-escalation study with potentially therapeutic activities of a (90)Y-labeled minigastrin derivative at 4 to 6-week intervals (30-50 mCi/m(2) per injection for a maximum of 4 injections). Hematologic and renal toxicities were identified as the dose-limiting toxicities at the 40 and 50 mCi/m(2) levels. Two patients experienced partial remissions, and 4 experienced stabilization of their previously rapidly progressing disease. These data suggest that CCK-B receptor ligands may be a useful new class of receptor-binding peptides for diagnosis and therapy of a variety of (CCK-B receptor expressing) tumor types. They allow for sensitive and reliable staging of patients with metastatic MTC. Initial therapeutic results are promising, but nephrotoxicity is a major concern to be solved.

Animals↗
PubMed2002

Correlation of red marrow radiation dosimetry with myelotoxicity: empirical factors influencing the radiation-induced myelotoxicity of radiolabeled antibodies, fragments and peptides in pre-clinical and clinical settings.

Usually, the red marrow (RM) is the first dose-limiting organ in systemic radionuclide therapy, e.g., radioimmuno-or radiopeptide therapy. However, several studies have obtained rather poor correlations between the marrow doses and the resulting toxicities. Red marrow doses are mostly not determined directly, but are derived from blood or whole-body doses. The aim of our recent work was to analyze, in a nude mouse model in more detail, additional factors than just total dose, such as dose rate or relative biological effectiveness (RBE) factors, that may influence the resulting myelotoxicity. Furthermore, we wanted to analyze, whether correlations between the red marrow doses and the resulting myelotoxicities can be found in clinical metabolic endo-radiotherapy. The maximum tolerated activities (MTAs) and doses (MTDs) of several murine, chimeric and humanized immunoconjugates as complete IgG or fragments (F(ab)(2), Fab), as well as peptides, labeled with beta(-)- (such as (131)I or (90)Y), Auger electron- (such as (125)I or (111)In), or alpha-emitters (such as (213)Bi) were determined in nude mice. Blood counts were monitored at weekly intervals; bone marrow transplantation (BMT) was performed in order to support the assumption of the RM as dose-limiting. The radiation dosimetry was derived from biodistribution data of the various conjugates, accounting for cross-organ radiation; the activities in the blood, bone, bone marrow, and major organs were determined over time. Dosimetry and myelotoxicity data of three clinical radioimmunotherapy trials, involving a total of 82 colorectal cancer patients, treated with (131)I-labeled anti-CEA IgG, and twelve non-Hodgkin's lymphoma patients, treated with (131)I-labeled anti-CD20 IgG, were analyzed. In the preclinical model, at the respective MTAs, the RM doses differed significantly between the three conjugates: e.g., with (131)I-labeled conjugates, the maximum tolerated activities were#10; 260 microCi for IgG, 1200 microCi for F(ab)(2), and 3 mCi for Fab, corresponding to blood doses of 17 Gy, 9 Gy, and 4 Gy, respectively. However, initial dose rates were 10 times higher with Fab as compared to IgG, and still 3 times higher as compared to F(ab)(2); interestingly, all 3 deliver approximately 4 Gy within the first 24 h. The MTDs of all three conjugates were increased by BMT by approximately 30%. Similar observations were made for the (90)Y-labeled conjugates. Higher blood-based RM doses were tolerated with Auger-emitters than with conventional beta(-)-emitters, whereas the MTDs were similar between alpha- and beta(-)-emitters. In accordance to dose rates never exceeding those occurring at the single injection MTA, re-injections of (131)I-, (90)Y-, or (213)Bi-labeled Fab' were tolerated without increased lethality, if administered 24-48 h apart, whereas reinjection of bivalent conjugates was not possible. Clinically, a sigmoidally shaped dose-effect correlation was found in colorectal cancer patients treated with (131)I-anti-CEA IgG. Previous mitomycin chemotherapy was identified as additional myelosensitizing factor leading to enhanced myelotoxicity. At comparable doses, non-Hodgkin's lymphoma patients developed higher degrees of myelotoxicity with a less clearly pronounced predictability from red marrow doses. In summary, results in the murine model suggest a strong influence of the dose rate (or better: dose per unit time), not only total dose on the resulting myelotoxicity, whereas the influence of high- (alpha, Auger/conversion electrons) versus low-LET (beta,gamma) type radiation seems to be much lower than expected from previous in vitro data. The lower myelotoxicity of Auger e(-) emitters is probably due to the short path length of their low-energy electrons, which cannot reach the nuclear DNA if the antibody is not internalized into the stem cells of the red marrow. Clinically, additional factors than just marrow dose (e.g., previous myelotoxic therapy, bone marrow involvement by metastatic malignancy) seem to a, bone marrow involvement by metastatic malignancy) seem to affect the resulting myelotoxicity.

Animals↗
PubMed2002

99mTc-HMPAO-labeled autologous versus heterologous leukocytes for imaging infection.

UNLABELLED: Radiolabeled autologous leukocytes are the gold standard for imaging infectious foci in patients. Good results have also been reported for radiolabeled heterologous leukocytes from noninfected donors. Until now, the 2 methods have not been directly compared. In this study, we compared the infection-imaging potential of 99mTc-hexamethylpropyleneamine oxime (HMPAO)-labeled autologous granulocytes with that of 99mTc-HMPAO-labeled granulocytes from either infected or noninfected donors in rabbits with Escherichia coli infection. METHODS: The radiolabeled granulocyte preparations were studied in rabbits with an E. coli infection in the left calf muscle. The soft-tissue infections were scintigraphically visualized after injection of 18 MBq of either 99mTc-HMPAO purified autologous granulocytes or radiolabeled purified heterologous granulocytes from infected or noninfected donor rabbits. Gamma camera images were acquired at 2 min and at 1, 2, and 4 h after injection. After the last image, the rabbits were killed and uptake of the radiolabel in the dissected tissues was determined. RESULTS: The 99mTc-HMPAO autologous granulocytes and heterologous granulocytes from infected donors accurately revealed the infectious focus in the calf muscle at 2 h after injection. At 4 h after injection, a significantly better (P < 0.05) delineation of the infection was established with the 99mTc-HMPAO autologous granulocytes and 99mTc-HMPAO heterologous granulocytes from the infected rabbits than with the heterologous granulocytes from noninfected donors. With both cell preparations, the intensity of uptake in the infected calf muscle continuously increased until 4 h after injection. The 99mTc-HMPAO heterologous granulocytes from noninfected donors showed no significant increase in contrast after 2 h after injection. Absolute uptake in the infected calf muscle was much higher for 99mTc-HMPAO autologous granulocytes (7.81 +/- 1.21 percentage injected dose [%ID]) and 99mTc-HMPAO heterologous infected granulocytes (8.91 +/- 1.92 %ID) than for the radiolabeled heterologous noninfected granulocytes (2.32 +/- 0.75 %ID) (P < 0.04) at 4 h after injection. The ratio of infected muscle to noninfected contralateral muscle was significantly higher for 99mTc-HMPAO autologous granulocytes and 99mTc-HMPAO heterologous granulocytes from infected donors than for 99mTc-HMPAO heterologous granulocytes from noninfected donors (5.53 +/- 1.09, 3.86 +/- 0.75, and 1.86 +/- 0.31, respectively; P < 0.05). CONCLUSION: For nuclear medicine imaging of infection, purified granulocytes derived from infected rabbits are superior to purified granulocytes derived from noninfected donor rabbits. In addition, autologous granulocytes gave similar results to heterologous granulocytes from infected donor rabbits, suggesting the need for intrinsic cell activation for specific granulocyte migration.

Abscess↗
PubMedDate not supplied

Two technetium-99m-labeled cholecystokinin-8 (CCK8) peptides for scintigraphic imaging of CCK receptors.

A broad spectrum of radiolabeled peptides with high affinity for receptors expressed on tumor cells is currently under preclinical and clinical investigation for scintigraphic imaging and radionuclide therapy. The present paper evaluates two (99m)Tc-labeled forms of the C-terminal octapeptide of cholecystokinin (CCK8): sulfated (s)CCK8, with high affinity for CCK1 and CCK2 receptors, and nonsulfated (ns)CCK8, with high affinity for CCK2 receptors but low affinity for CCK1 receptors. Peptides were conjugated with the bifunctional chelator N-hydroxysuccinimidyl hydrazino niconitate (s-HYNIC). (99m)Tc-labeling, performed in the presence of nicotinic acid and tricine, was highly efficient (approximately 95%) and yielded products with a high specific activity (approximately 700 Ci/mmol) and good stability (approximately 5% release of radiolabel during 16 h incubation in phosphate buffered saline at 37 degrees C). Chinese hamster ovary cells stably expressing the CCK1 receptor (CHO-CCK1 cells) internalized approximately 3% of added (99m)Tc-sCCK8 per confluent well during 2 h at 37 degrees C. Internalization was effectively blocked by excess unlabeled sCCK8. CHO-CCK1 cells did not internalize (99m)Tc-nsCCK8. Displacement of (99m)Tc-sCCK8 and -nsCCK8 by unlabeled CCK-8 (performed at 0 degrees C to prevent internalization) revealed 50% inhibitory concentrations (IC(50)) of 8 nM and >1 microM, respectively. CHO-CCK2 cells internalized approximately 25% and approximately 5% of added (99m)Tc-sCCK8 and -nsCCK8, respectively. In both cases internalization was blocked by excess unlabeled peptide. IC(50) values for the displacement of (99m)Tc-sCCK8 and -nsCCK8 were 3 nM and 10 nM, respectively. CHO-CCK1 cell-derived tumors present in one flank of athymic mice accumulated 2.0% of injected (99m)Tc-sCCK8 per gram tissue at 1 h postinjection. This value decreased to 0.6% following coinjection with excess unlabeled peptide. Uptake of (99m)Tc-nsCCK8 was low (0.2%) and not did change by excess unlabeled peptide (0.3%). Accumulation of (99m)Tc-sCCK8 and -nsCCK8 by CHO-CCK2 cell-derived tumors (present in the other flank) amounted to 4.2% and 0.6%, respectively. In both cases uptake was significantly reduced by excess unlabeled peptide to 1.0% and 0.4% for sCCK8 and nsCCK8, respectively. Accumulation of (99m)Tc-sCCK8 was also high in pancreas (11.7%), stomach (2.0%), and kidney (2.1%), whereas uptake of (99m)Tc-nsCCK8 was high in stomach (0.7%) and kidney (1.4%). Both radiolabeled peptides showed a rapid blood clearance. In conclusion, these data show that CCK8 analogues can be efficiently labeled with (99m)Tc using s-HYNIC as chelator and nicotinic acid/tricine as coligand system without compromising receptor binding. Furthermore, the present study demonstrates that CCK1 tumors hardly accumulate (99m)Tc-nsCCK8, CCK2 tumors accumulate 2 times more (99m)Tc-sCCK8 than CCK1 tumors, and CCK2 tumors accumulate 15 times more (99m)Tc-sCCK8 than (99m)Tc-nsCCK8. Although accumulation in some nontarget organs was also higher with (99m)Tc-sCCK8, this may not reflect the human situation due to a different receptor expression pattern in humans as compared to mice. Therefore, further studies are warranted to investigate the possible use of (99m)Tc-sCCK8 for scintigraphic imaging of CCK receptor-positive tumors in humans.

Animals↗
PubMedDate not supplied

Two-photon absorption-controlled multidose drug release: a novel approach for secondary cataract treatment.

Tens of millions of cataract surgeries are done every year and the number is increasing heavily. Posterior capsule opacification is the major postoperative complication with an incidence of 10 to 50% within 5 years, depending on the age of the patient. We present a novel approach for secondary cataract treatment in a noninvasive manner. Photochemically triggered drug release from a polymer enables repeated drug applications for cataract treatment years after implantation of the intraocular lens, just when needed. However, light in the visible spectral range must pass through the lens but must not induce drug release. We demonstrate that two-photon absorption photochemistry is a powerful tool to overcome this problem. With wavelengths in the visible regime, a photochemical reaction that requires energies in the UV is triggered. The high intensities needed for this process never occur in any lighting condition in daily lives, but may be easily obtained with focused laser beams routinely used in ophthalmology. The properties of the therapeutic system are specified and the function is demonstrated by in-vitro cell tests. Noninvasive multidose photochemically triggered drug release from implanted intraocular lenses carrying a drug depot may be a therapeutic as well as an economic choice to established treatments of secondary cataracts.

Cataract↗