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O C Boerman

Publications and source records attributed to O C Boerman.

At least 109 records · Page 6Linked to original sources
PubMed1996

Labelled Stealth liposomes in experimental infection: an alternative to leukocyte scintigraphy?

Indium-111 (111In) and technetium-99m (99Tcm) Stealth liposomes were compared with 111In- and 99Tcm-labelled white blood cells (WBC) in experimental infection in a rabbit model. Preformed polyethylene glycol-coated liposomes and separated WBC were radiolabelled with either 111In-oxine or 99Tcm-hexamethylpropyleneamine oxime (99TcM-HMPAO). After the intravenous administration of one of the four radiopharmaceuticals to rabbits with focal Staphylococcus aureus infection, scintigraphic images were recorded at various time points post-injection and the biodistribution of the radiopharmaceuticals was determined. At 4 h post-injection, uptake of 111In-WBC in the abscess was significantly higher than that of the three other products. AT later time points, 111In-WBC, 111In-liposome and 99Tcm-liposome uptake in the abscess were similar. In contrast, a 20 h post-injection, uptake of 99Tcm-WBC was significantly lower. The abscess-to-background ratios showed a similar pattern to the absolute abscess uptake: initial high values for 111In-WBC, a more gradual increase over time of the liposome preparations to the level of 111In-WBC and persistently low values for 99Tcm-WBC. Clearance from the blood of both labelled WBC preparations was significantly faster and splenic uptake significantly higher compared with those of the labelled liposomes. In conclusion, given the similar in vivo characteristics of labelled liposomes and labelled WBC, labelled liposomes may be an attractive replacement for labelled WBC, providing a continuously available, high-quality, 99Tcm-labelled radiopharmaceutical that can be prepared easily without any need to handle blood.

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PubMed1996

Detecting infection and inflammation with technetium-99m-labeled Stealth liposomes.

UNLABELLED: The performance of 99mTc Stealth liposomes was investigated in various rat models. METHODS: Preformed polyethyleneglycol-containing liposomes with encapsulated reduced glutathione, were radiolabeled using the lipophilic 99mTc-HMPAO. The labeled liposomes were intravenously administered to rats with focal S. aureus or E. coli infection, or turpentine-induced inflammation. For comparison, Tc-99m-nanocolloid- and 99mTc-labeled nonspecific IgG were tested. In rats with Pneumocystis carinii pneumonia (PCP), Tc-99m-liposomes were directly compared to In-111 labeled nonspecific IgG. RESULTS: Technetium-99m-liposomes accumulated in the infectious and inflammatory muscle foci over 24 hr (0.59% injected dose per gram tissue (%ID/g) for S. aureus; 1.18 %ID/g for turpentine). Abscess-to-muscle ratios increased to values as high as 24.0, 41.7 and 44.5 for the respective models at 24 hr postinjection. Technetium-99m-liposomes visualized the foci as early as 1 hr postinjection. Technetium-99m-IgG visualized S. aureus infection, but abscess-to-muscle ratios and abscess uptake at the later time points were significantly lower. Technetium-99m-nanocolloid failed to visualize any of the muscle foci. In PCP however, 99mTc-liposomes did not show preferential localization in the infection. The control agent 111In-IgG showed a significant, two-fold increase in lung uptake. CONCLUSION: Technetium-99m-Stealth liposomes preferentially accumulated in abscesses, leading to very high target-to-nontarget ratios. This property appears to be related to a process based on uptake of long-circulating particles. In a specific type of infection, i.c. PCP, 99mTc-liposomes did not accumulate in diseased lung tissue, thus mimicking the in vivo behavior of labeled leukocytes.

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PubMed1995

Development and characterization of anti-renal cell carcinoma x antichelate bispecific monoclonal antibodies for two-phase targeting of renal cell carcinoma.

To test a two-step approach for radioimmunotargeting of renal cell cancer, quadroma cells secreting antichelate x anti-renal cell carcinoma bispecific antibodies were obtained by somatic cell fusion. Five monoclonal antibodies against the chelate 1,4,7-triazaheptane-N,N',N"-pentaacetic acid (DTPA) were produced and characterized. Competitive binding assays indicated that the anti-DTPA antibodies reacted with DTPA chelated with indium, yttrium, chromium, iron, or zinc. The affinity constants of the anti-DTPA antibodies for 111In-DTPA ranged from 0.19 to 0.23 nM-1. Using different chelates, a remarkable chelate specificity of the anti-DTPA antibodies was demonstrated. The chelates recognized by the antibodies DTIn1, DTIn2, and DTIn4 share a N(N")-diacetic acid group, whereas the chelates recognized by DTIn3 share a N'-acetic acid group, suggesting the presence of different essential structures within the DTPA molecule that determine the reactivity of the antibodies. Five anti-DTPA antibody-producing hybridomas were used for somatic cell fusion with hybridoma G250 directed against renal cell carcinoma, resulting in three bispecific antibody-producing quadroma cell lines. The bispecific monoclonal antibodies were purified from ascites fluid using protein A affinity chromatography followed by hydroxylapatite chromatography and/or cation exchange chromatography. Of the total IgG amount present in the ascites fluid, 10-15% represented the bispecific antibodies. These bispecific antibodies will allow testing and optimization of a two-step approach for radioimmunotargeting of chelated radionuclides.

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PubMed1995

Recombinant human IL-7 administration in mice affects colony-forming units-spleen and lymphoid precursor cell localization and accelerates engraftment of bone marrow transplants.

Murine reconstitution assays were used to investigate the effects of recombinant human interleukin-7 (rhIL-7) on myeloid and lymphoid precursors and on bone marrow engraftment. Reconstitution with bone marrow from rhIL-7-treated mice results in a 3.4-fold decrease in total colony-forming unit-spleen (CFU-S) activity (day 9) and an 18.1- and 11.9-fold decrease in its ability to generate thymocytes and splenic B lineage cells, respectively. In contrast, after reconstitution with splenocytes from rhIL-7-treated mice, CFU-S activity increased 23.6-fold (day 9) and the thymocyte and splenic B lineage cell regenerative capacity increased by 4.0- and 3.2-fold, respectively. In addition, CD43low+, B220low+ cells that contain pre-pro-B cells and pro-B cells were expanded two- to threefold and Ig mu-, B220+, CD2- and Ig mu-, B220+, CD2+ B lineage cells were expanded approximately 10-fold and 10- to 45-fold (depending on the tissue examined), respectively, after rhIL-7 treatment. Administration of rhIL-7 to irradiated mice transplanted with bone marrow resulted in accelerated T cell and B cell reconstitution by up to 2-4 weeks. Thus, rhIL-7 administration affects the distribution of myeloid and lymphoid precursors. Moreover, rhIL-7 administration accelerates murine bone marrow cell engraftment and therefore may be useful in reducing the engraftment time in bone marrow transplant patients.

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PubMed1995

Specific targeting of infectious foci with radioiodinated human recombinant interleukin-1 in an experimental model.

In the present study, radioiodinated human recombinant interleukin-1 (IL-1) was investigated for its potential to image infectious foci in vivo in an animal model of infection. Twenty-four hours after induction of a Staphylococcus aureus abscess in the left calf muscle, mice were i.v. injected with both iodine-125 labelled IL-1 and iodine-131 labelled myoglobin, a size-matched control agent. The animals were killed for tissue biodistribution studies at 2, 6, 12, 24 and 48 h p.i. Gamma camera images were obtained at 6, 24 and 48 h after injecting mice with 123I-IL-1. Radioiodinated IL-1 rapidly cleared from the body; after 12 h the abscess was the organ with the highest activity. The absolute abscess uptake of 125I-IL-1 remained high compared to 131I-myoglobin, resulting in significantly higher abscess-to-muscle ratios of 125I-IL-1 compared to 131I-myoglobin. The ratios of 125I-IL-1 reached the ultimate value of 44.4+/-10.8 at 48 h p.i., whereas the ratios of 131I-myoglobin did not exceed 5.9+/-0.7. Gamma camera imaging revealed clearly visible abscesses. In conclusion, our results demonstrate specific retention of radioiodinated IL-1 in the abscess, presumably by interaction of IL-1 with its receptor on the inflammatory cells. The high target-to-background ratios that were obtained over the course of time indicate that the IL-1 receptor may be a valuable target for the imaging of infectious foci.

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PubMed1995

Dissociation of indium from indium-111-labelled diethylene triamine penta-acetic acid conjugated non-specific polyclonal human immunoglobulin G in inflammatory foci.

Several investigators have reported retention of indium-111 in infectious foci after intravenous injection of 111In-labelled immunoglobulin G (IgG). With this study we intended to test the hypothesis that, upon administration of 111In-diethylene triamine penta-acetic acid (DTPA-IgG), 111In is retained in the infectious foci after dissociation from IgG. Therefore we measured the tissue distribution of double-labelled 111In-DTPA-IgG-(carbon-14) in rats with a focal infection and compared the results with corresponding data for DTPA-IgG-(14C). DTPA-conjugated IgG was labelled with 111In via citrate transchelation. 111In-DTPA-IgG and DTPA-IgG were labelled with 14C through methylation. High-performance liquid chromatography (HPLC) and instant thin-layer chromatography analysis were performed to test the in vitro stability of the labelled proteins. Young Wistar rats with a Staphylococcus aureus infection of the left calf muscle were injected intravenously with 0.2 ml of a solution containing either 0.4 MBq 111In and 30 kBq 14C or 30 kBq 14C labelled to 80 micrograms IgG. Groups of five rats were sacrificed at 2, 6, 24, and 48 h. p.i. Activity uptake was determined for plasma, urine, abscess, muscle and various other tissues. Averages and standard deviations were calculated for groups of five rats. HPLC analysis was performed on plasma and urine samples taken up to 48 h p.i. The radiochemical purity of the IgG preparations was > 95%. The labelled preparations appeared stable in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)

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PubMed1995

Humoral anti-OV-TL 3 response after the intravenous administration of radiolabelled Fab' or F(ab')2 fragments in ovarian cancer patients.

The human anti-mouse antibody (HAMA) response was determined in the serum of patients suspected of having ovarian cancer who underwent radioimmunoscintigraphy with either 99Tcm-OV-TL 3 Fab' (n = 20) or 111In-DTPA-OV-TL 3 F(ab')2 (n = 73). Blood samples were collected prior to and at several time points post-intravenous injection. The detection of HAMA was performed with an in-house OV-TL 3 F(ab')2-based sandwich-type immunoradiometric assay (IRMA). The homologous IRMA demonstrated that 8 of 20 (40%) patients had developed HAMA responses after injection of Fab' fragments and that 14 of 73 (19%) patients had developed HAMA responses after F(ab')2 administration. The subclass of the measured HAMA was analysed in a limited number of samples, showing IgG or IgM as well as mixed responses. The kinetics of the HAMA responses varied greatly. Our study showed the relevance of the sampling time and frequency: HAMA responses can be easily underestimated with a low sampling frequency. The homologous IRMA described in this study was able to quantify the OV-TL 3-specific HAMA responses. With additional assays, the subclass of the HAMA could be further analysed. Remarkably, the fraction of HAMA responders after injection of OV-TL 3 Fab' fragments was in the same range as the proportion of HAMA responders after F(ab')2 administration.

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PubMed1995

Sterically stabilized liposomes labeled with indium-111 to image focal infection.

UNLABELLED: To determine the potential of sterically stabilized liposomes to image infectious and inflammatory foci, the in vivo behavior of 111In-labeled PEGylated (coated with polyethylene glycol) liposomes was studied in a rat model. METHODS: Indium-111-PEGylated lipsomes were administered intravenously to rats infected with S. aureus in the left calf muscle. The distribution of the radiolabel was studied by gamma counting of dissected tissues and gamma camera imaging for 48 hr. As a reference agent, the preparation of 111In-IgG was included in these studies. RESULTS: Clearance of the PEGylated liposomes from the blood compartment was similar to the clearance of 111In-IgG in this model (t1/2 approximately 20 hr). Uptake of the radiolabel in the abscess with the 111In-liposomes was twice as high as the uptake following injection of 111In-IgG (2.7%ID/g versus 1.1%ID/g at 48 hr postinjection). Tissue counting revealed that abscess-to-muscle ratios reached values up to 20 and 34 (24 and 48 p.i., respectively). As early as 1 hr postinjection, the abscess could be visualized scintigraphically. CONCLUSION: The in vivo characteristics of this liposomal formulation in this rat model indicate that sterically stabilized liposomes labeled with gamma emitters might be a valuable addition to the arsenal of radiopharmaceuticals currently used for infection imaging.

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PubMed1994

Differential gene expression for IL-1 receptor antagonist, IL-1, and TNF receptors and IL-1 and TNF synthesis may explain IL-1-induced resistance to infection.

IL-1 pretreatment prolongs survival in lethal infection in normal and in neutropenic mice. We investigated whether this protection occurs by interference with deleterious cytokine effects. The effect of IL-1 pretreatment on concentrations of IL-1 alpha, IL-1 beta, IL-6, and TNF-alpha circulating in vivo and the ex vivo cytokine production capacity of macrophages was assessed in uninfected, non-neutropenic and neutropenic Swiss mice, in Swiss mice infected with Klebsiella pneumoniae (non-neutropenic mice) or Pseudomonas aeruginosa (neutropenic mice), and in neutropenic C3H/HeN and C3H/HeJ mice infected with P. aeruginosa. In Swiss and C3H/HeN mice, IL-1 pretreatment enhanced survival and reduced circulating TNF-alpha and IL-6 as well as LPS-stimulated production of IL-1 alpha and TNF-alpha. In C3H/HeJ mice, a lack of IL-1-induced protection was associated with low cytokine concentrations and production. In contrast, up-regulation of mRNA for the IL-1 receptor antagonist (IL-1Ra) was observed in several organs of IL-1-pretreated mice, suggesting that IL-1Ra could attenuate deleterious IL-1 effects. In addition, IL-1 pretreatment down-regulated steady state mRNA for the type I IL-1R and the type I TNFR in several organs at the time of infection, suggesting desensitization of target cells as an additional mechanism of IL-1-induced protection. We conclude that the IL-1-induced protection is at least partially mediated by down-regulating cytokine production, and that the induction of IL-1Ra and the desensitization of target cells by receptor down-modulation may also contribute to this phenomenon.

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PubMed1994

Effect of the route of administration on the biodistribution of radioiodinated OV-TL 3 F(ab')2 in experimental ovarian cancer.

The effect of the route administration on the distribution of radioiodinated OV-TL 3 F(ab')2 was studied in Balb/c female mice with intraperitoneal or subcutaneous ovarian carcinoma xenografts. In the intraperitoneal tumour model in which both ascites and solid tumour deposits were present, intraperitoneal administration resulted in a lower estimated radiation dose to blood as compared with intravenous administration. In this model normalization to equal estimated radiation doses to blood for both routes of administration indicated that a twice as high estimated radiation dose can be guided to solid intraperitoneal tumour deposits following intraperitoneal administration. Evacuation of ascitic tumour cells prior to monoclonal antibody injection further increased the estimated radiation dose to solid intraperitoneal tumour deposits following intraperitoneal delivery. Following simultaneous intravenous and intraperitoneal injection of the monoclonal antibody, tissue uptake showed no relevant differences in the subcutaneous tumour model. Overall, the intraperitoneal route of administration was found to be the best choice for therapeutic delivery of iodine-131 labelled monoclonal antibodies.

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PubMed1994

Decreased kidney uptake of technetium-99m-labelled Fab' fragments in ovarian carcinoma bearing nude mice using a cleavable chelator.

A new 99mTc labelling method using a cleavable chelator, RP-1, was developed. In this study Balb/c mice with ovarian carcinoma xenografts received various Fab' fragments labelled with 99mTc either directly or via RP-1. Kidney uptake was significantly lower for the RP-1 linked conjugates. Tumour uptake showed no significant differences between RP-1 conjugates and directly labelled preparations. In conclusion, with the use of the cleavable linker RP-1, kidney uptake can be reduced significantly resulting in a lower radiation dose to the kidneys.

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PubMed1994

Is somatostatin receptor scintigraphy suited to detection of acute infectious disease?

Fast and accurate delineation of acute infectious foci is very important for adequate management of patients. All currently available scintigraphic techniques require a relatively long timespan between referral to the nuclear medicine department and final diagnosis. Small peptides that bind to receptors on cells in the infectious focus might improve the diagnostic possibilities. Since activated leukocytes express somatostatin receptors, 111In-octreotide, a somastostatin analogue, was tested for its usefulness in detecting acute infection in rats with a calf muscle infection caused by Staphylococcus aureus. 111In-octreotide was compared with the much larger protein 111In-labelled human nonspecific immunoglobulin G (111In-IgG). As early as 0.5 h after injection, the 111In-octreotide uptake in the abscess was significantly lower than that of 111In-IgG. Moreover, no 111In-octreotide retention in the abscess over time was noted. In conclusion, somatostatin receptor imaging does not allow scintigraphic detection of an acute infectious lesion. The uptake in an abscess is relatively poor compared to 111In-IgG.

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PubMed1992

The presence of a concomitant bulky tumor can decrease the uptake and therapeutic efficacy of radiolabeled antibodies in small tumors.

We describe the effects that a concomitant large tumor mass can exert on the therapeutic efficacy of radioimmunotherapy against small tumors, using the nude mouse/GW-39 human colonic cancer model. The tumor uptake 7 days p.i. of i.v.-injected 131I-labeled anti-CEA MAb (NP-4) and anti-CSAp MAb (Mu-9) in small (less than 0.2 g) s.c. GW-39 tumors was approximately 3-fold lower in animals with a concomitant large (greater than 1.0 g) GW-39 tumor than in the absence of a large tumor. An inverse correlation between the mass of the tumor burden and the 131I levels in the blood was observed, indicating that a large tumor mass may act as a sink for the injected radiolabeled antibody. Increasing antibody protein dose did not reverse the reduced uptake in the small s.c. tumors. The therapeutic efficacy of a single 0.25-mCi injection of 131I-labeled anti-CSAp MAb Mu-9 towards intrapulmonary GW-39 metastases was tested in nude mice bearing either small or large GW-39 s.c. tumors. Over 80% of the animals with small s.c. GW-39 tumors survived 18 weeks after tumor transplantation, whereas less than 20% of the animals bearing large s.c. tumors survived past 13 weeks. Dosimetric calculations, based on biodistribution data over time, indicated that the presence of a large s.c. tumor mass may have decreased the radiation dose to the intrapulmonary tumors almost two-fold. However, the radiation dose to the blood was also decreased in the animals with the large tumor burden. Therefore, the animals with larger tumor burden may also have been able to sustain higher doses of the radioantibody. The presence of a large tumor mass can thus affect the biodistribution and therapeutic efficacy of radioiodinated antibodies. We suggest that bulky tumors can adsorb a considerable amount of the injected dose, thereby reducing the total amount of MAb available for binding to the smaller tumors.

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PubMed1992

Enhanced clearance of radiolabeled murine monoclonal antibody by a syngeneic anti-idiotype antibody in tumor-bearing nude mice.

A syngeneic anti-idiotype monoclonal antibody (MAb) (CM-11) directed against an anti-carcinoembryonic antigen (CEA) murine MAb (NP-4) was evaluated as a second antibody (SA) to promote the rapid clearance of radiolabeled NP-4 from the blood. Initial studies confirmed that CM-11 IgG removed 131I-NP-4 IgG from the blood as effectively as a polyclonal donkey anti-goat IgG removed 131I-goat IgG. However, use of an F(ab')2 in place of either the NP-4 or CM-11 IgG was not as effective in removing primary radiolabeled antibody, despite the formation of high-molecular-weight complexes. In accordance with previous results, the timing and dose of the SA injection was critical for optimizing tumor uptake and improving tumor/non-tumor ratios. In nude mice bearing GW-39 human colonic tumor xenografts, a delay in the injection of CM-11 by 48 hr after injection of radiolabeled NP-4 was optimal, since this allowed maximum tumor accretion. At a 200:1 CM-11:NP-4 ratio, tumor uptake was reduced, suggesting inhibition of NP-4 binding to CEA within the tumor. Despite optimizing tumor uptake by delaying SA injection and adjusting its dose, the percentage of 131I-NP-4 in the tumor decreased 2- to 3-fold within 2 days after CM-11 injection. A similar effect was seen for 111In-labeled NP-4 IgG with CM-11. Injection of excess unlabeled NP-4 given to block CM-11 shortly after its injection failed to curtail the loss of NP-4 from the tumor. Our results suggest that high blood levels of MAb are important for sustaining NP-4 in the tumor. Radiation-dose predictions derived from biodistribution studies indicate that a higher tumor dose may be delivered using the SA method than with either 131I-NP-4 IgG or F(ab')2 alone. Use of the SA method with 90Y-labeled NP-4 IgG, as modeled from biodistribution studies with 111In-NP-4 IgG, would likely be limited by liver toxicity.

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PubMed1992

Influence of antibody protein dose on therapeutic efficacy of radioiodinated antibodies in nude mice bearing GW-39 human tumor.

The biodistributions of three 131I-labeled murine monoclonal antibodies, NP-4 and Immu-14 anti(carcinoembryonic antigen), and Mu-9 anti-(colon-specific antigen p), were determined at antibody protein doses varying from 1 microgram to 1000 micrograms in nude mice with small (0.1-0.4 g) GW-39 human colonic cancer xenografts. For each antibody, the percentage of the injected dose per gram of tumor and tumor/nontumor ratios were constant over a wide protein dose range. However, at high protein doses (above 100 micrograms for NP-4 and Immu-14) the percentage of the injected dose per gram of tumor and tumor/nontumor ratios decreased. Assuming that the uptake of a control anti-(alpha-fetoprotein) antibody represents the amount of antibody that accumulates in the tumor nonspecifically (i.e., antigen-independently), it could be shown that for each antibody the amount of antibody protein that accumulates in the tumor specifically, increases linearly with the protein dose, reaching a plateau level at the highest doses tested. The growth inhibition of GW-39 tumor transplants in nude mice treated with 131I-labeled antibody at either low or high antibody protein dose was compared. These experiments indicated that, in this experimental model, enhanced antibody protein dose may decrease the therapeutic efficacy of radioiodinated antibodies. It is suggested that heterogeneous distribution at low protein dose, with intense localization around the blood vessels, may enhance the tumoricidal effect of radioantibodies.

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PubMed1991

Biodistribution of a monoclonal antibody (RNL-1) against the neural cell adhesion molecule (NCAM) in athymic mice bearing human small-cell lung-cancer xenografts.

The purpose of this investigation was to determine the targeting potential of the murine monoclonal antibody (MAb) RNL-1 for human small-cell lung cancer (SCLC) in a nude mouse model. RNL-1 is preferentially reactive with SCLC and lung carcinoids, and was classified as a cluster-1 MAb as defined by the International Workshop on Small-Cell Lung-Cancer Antigens. From the intercellular location of the target antigen and its reactivity with 3T3 cells transfected with nucleic acid sequences encoding for the neural cell adhesion molecule (NCAM), it was concluded that RNL-1 is directed against NCAM. RNL-1 was radiolabelled with either 125iodine or 111indium and injected into nude mice bearing NC1-H82 SCLC xenografts. The biodistribution of the radiolabels was determined up to 120 hr post injection. Maximum tumour accretion for 111In-RNL-1 was 11.8%ID/g and 6.5%ID/g for 125I-RNL-1. The accumulation of 111In-RNL-1 could be visualized clearly by gamma scintigraphy without background subtraction techniques. Autoradiographs of whole-body sections from animals injected with 125I-RNL-1 showed that activity in the SCLC xenografts was mainly peripheral, suggesting that tumour uptake is dependent on the vascularization of the tumour tissue.

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