Biomedical subjects

Marek Kosinski

Publications and source records attributed to Marek Kosinski.

7 recordsLinked to original sources

PubMed2006

Cytostatic lung perfusion results in heterogeneous spatial regional blood flow and drug distribution: evaluation of different cytostatic lung perfusion techniques in a porcine model.

OBJECTIVES: Comparison of doxorubicin uptake, leakage and spatial regional blood flow, and drug distribution was made for antegrade, retrograde, combined antegrade and retrograde isolated lung perfusion, and pulmonary artery infusion by endovascular inflow occlusion (blood flow occlusion), as opposed to intravenous administration in a porcine model. METHODS: White pigs underwent single-pass lung perfusion with doxorubicin (320 mug/mL), labeled 99mTc-microspheres, and Indian ink. Visual assessment of the ink distribution and perfusion scintigraphy of the perfused lung was performed. 99mTc activity and doxorubicin levels were measured by gamma counting and high-performance liquid chromatography on 15 tissue samples from each perfused lung at predetermined localizations. RESULTS: Overall doxorubicin uptake in the perfused lung was significantly higher (P = .001) and the plasma concentration was significantly lower (P < .0001) after all isolated lung perfusion techniques, compared with intravenous administration, without differences between them. Pulmonary artery infusion (blood flow occlusion) showed an equally high doxorubicin uptake in the perfused lung but a higher systemic leakage than surgical isolated lung perfusion (P < .0001). The geometric coefficients of variation of the doxorubicin lung tissue levels were 175%, 279%, 226%, and 151% for antegrade, retrograde, combined antegrade and retrograde isolated lung perfusion, and pulmonary artery infusion by endovascular inflow occlusion (blood flow occlusion), respectively, compared with 51% for intravenous administration (P = .09). 99mTc activity measurements of the samples paralleled the doxorubicin level measurements, indicating a trend to a more heterogeneous spatial regional blood flow and drug distribution after isolated lung perfusion and blood flow occlusion compared with intravenous administration. CONCLUSIONS: Cytostatic lung perfusion results in a high overall doxorubicin uptake, which is, however, heterogeneously distributed within the perfused lung.

Animals↗

PubMed2005

Repeated injections of 131I-rituximab show patient-specific stable biodistribution and tissue kinetics.

PURPOSE: It is generally assumed that the biodistribution and pharmacokinetics of radiolabelled antibodies remain similar between dosimetric and therapeutic injections in radioimmunotherapy. However, circulation half-lives of unlabelled rituximab have been reported to increase progressively after the weekly injections of standard therapy doses. The aim of this study was to evaluate the evolution of the pharmacokinetics of repeated 131I-rituximab injections during treatment with unlabelled rituximab in patients with non-Hodgkin's lymphoma (NHL). METHODS: Patients received standard weekly therapy with rituximab (375 mg/m2) for 4 weeks and a fifth injection at 7 or 8 weeks. Each patient had three additional injections of 185 MBq 131I-rituximab in either treatment weeks 1, 3 and 7 (two patients) or weeks 2, 4 and 8 (two patients). The 12 radiolabelled antibody injections were followed by three whole-body (WB) scintigraphic studies during 1 week and blood sampling on the same occasions. Additional WB scans were performed after 2 and 4 weeks post 131I-rituximab injection prior to the second and third injections, respectively. RESULTS: A single exponential radioactivity decrease for WB, liver, spleen, kidneys and heart was observed. Biodistribution and half-lives were patient specific, and without significant change after the second or third injection compared with the first one. Blood T(1/2)beta, calculated from the sequential blood samples and fitted to a bi-exponential curve, was similar to the T(1/2) of heart and liver but shorter than that of WB and kidneys. Effective radiation dose calculated from attenuation-corrected WB scans and blood using Mirdose3.1 was 0.53+0.05 mSv/MBq (range 0.48-0.59 mSv/MBq). Radiation dose was highest for spleen and kidneys, followed by heart and liver. CONCLUSION: These results show that the biodistribution and tissue kinetics of 131I-rituximab, while specific to each patient, remained constant during unlabelled antibody therapy. RIT radiation doses can therefore be reliably extrapolated from a preceding dosimetry study.

Antibodies, Monoclonal↗

PubMed2004

Highly efficient DNA incorporation of intratumourally injected [125I]iododeoxyuridine under thymidine synthesis blocking in human glioblastoma xenografts.

Intratumoural (i.t.) injection of radio-iododeoxyuridine (IdUrd), a thymidine (dThd) analogue, is envisaged for targeted Auger electron- or beta-radiation therapy of glioblastoma. Here, biodistribution of [(125)I]IdUrd was evaluated 5 hr after i.t. injection in subcutaneous human glioblastoma xenografts LN229 after different intravenous (i.v.) pretreatments with fluorodeoxyuridine (FdUrd). FdUrd is known to block de novo dThd synthesis, thus favouring DNA incorporation of radio-IdUrd. Results showed that pretreatment with 2 mg/kg FdUrd i.v. in 2 fractions 0.5 hr and 1 hr before injection of radio-IdUrd resulted in a mean tumour uptake of 19.8% of injected dose (% ID), representing 65.3% ID/g for tumours of approx. 0.35 g. Tumour uptake of radio-IdUrd in non-pretreated mice was only 4.1% ID. Very low uptake was observed in normal nondividing and dividing tissues with a maximum concentration of 2.9% ID/g measured in spleen. Pretreatment with a higher dose of FdUrd of 10 mg/kg prolonged the increased tumour uptake of radio-IdUrd up to 5 hr. A competition experiment was performed in FdUrd pretreated mice using i.t. co-injection of excess dThd that resulted in very low tumour retention of [(125)I]IdUrd. DNA isolation experiments showed that in the mean >95% of tumour (125)I activity was incorporated in DNA. In conclusion, these results show that close to 20% ID of radio-IdUrd injected i.t. was incorporated in tumour DNA after i.v. pretreatment with clinically relevant doses of FdUrd and that this approach may be further exploited for diffusion and therapy studies with Auger electron- and/or beta-radiation-emitting radio-IdUrd.

Animals↗

PubMed2004

The preparation of clinical grade 5-[123I]iodo-2'-deoxyuridine and 5-[125I]iodo-2'-deoxyuridine with high in vitro stability and the potential for early proliferation scintigraphy.

BACKGROUND AND METHODS: 5-Iodo-2'-deoxyuridine (IdUrd) radiolabelled with the positron emitter I or with the gamma and Auger electron emitters I or I has been proposed for cancer diagnosis and therapy. We modified the synthesis to reliably obtain [I]IdUrd and [I]IdUrd by using an Iodogen supported destannylation reaction of 5-(tri-n-butylstannyl)-2'-deoxyuridine (Bu3SndUrd) which meets the requirements for good laboratory practice (GLP) and good clinical practice (GCP). A method of purification was developed to eliminate by-products as well as any unreacted starting material. RESULTS: [I]IdUrd, which originated from a trace of iodide in the Bu3SndUrd precursor, was identified as the unknown by-product reported for this method. This trace could be eliminated by modified purification of Bu3SndUrd. Stabilization of pH was essential for unequivocal identification of radiolabelled IdUrd and possible degradation products in the different systems tested for quality control. Biodistribution in tumour bearing nude mice was measured as early as 3 and 6 h after i.v. injection of [I]IdUrd. This compound showed high and specific activity uptake in tumour and dividing tissues when combined with 5-fluoro-2'-deoxyuridine pre-treatment. Uptake was specifically inhibited by injection of excess thymidine.

Animals↗

PubMed2004

131I-rituximab: relationship between immunoreactivity and specific activity.

UNLABELLED: As part of a search for optimal conditions for radioimmunotherapy of lymphoma, rituximab was labeled with 2 different specific activities of 131I and immunoreactivity was comparatively measured. METHODS: Labeling was performed with chloramine T using as starting conditions 185 MBq of 131I per 1 mg and per 5 mg of antibody for labelings A and B, respectively. Six comparative labelings were performed over a period of 10 mo with similar efficacy and purified by anion-exchange chromatography. Immunoreactivity was determined immediately after labeling in parallel assays using different concentrations of fresh Raji and Daudi cells. Results were compared at maximal observed specific binding on 10(7) cells and after extrapolation to infinite antigen excess. A statistical analysis was performed to predict the frequency of radiolabeled mono- and polyiodinated antibodies: First, a gaussian distribution predicted the number of iodine atoms per antibody in labelings A and B, respectively; then, the radiolabeling probability was developed according to the Newton binome. RESULTS: Final radiochemical purity was >98.4% for all labelings. The final mean specific activities were 169.7 MBq/mg and 32.8 MBq/mg, corresponding to 0.87 and 0.17 iodine atoms per antibody in labelings A and B, respectively. Labeling B showed a significantly higher immunoreactivity than did labeling A, the mean relative increase in binding being > or =28% for both Raji cells and Daudi cells. The predictive statistical analysis indicated that 57.3% and 15.4% of radiolabeled antibodies in labelings A and B, respectively, were polyiodinated. CONCLUSION: The low specific activity of 131I-rituximab allowed preservation of a high immunoreactivity and correlated with the prediction of a low percentage of polyiodinated radiolabeled antibodies.

Antibodies, Monoclonal↗

PubMed2003

Radiolabeled neurotensin analog, 99mTc-NT-XI, evaluated in ductal pancreatic adenocarcinoma patients.

UNLABELLED: The study aim was to assess the safety, biodistribution, tissue kinetics, and tumor uptake of the (99m)Tc-labeled neurotensin (NT) analog NT-XI. METHODS: Four patients presenting ductal pancreatic adenocarcinoma were studied with (99m)Tc-NT-XI. Patients were followed by scintigraphy up to 4 h and by continued blood and urinary sampling until surgery 18-22 h after injection. Surgical tissue samples were analyzed for radioactivity uptake and NT receptor expression. RESULTS: No side effects were observed on injection of (99m)Tc-NT-XI. Blood biologic half-lives alpha and beta were 35 min (range, 17-62 min) and 230 min (range, 107-383 min), respectively. Repeated whole-body scintigraphy performed in 2 patients showed a single exponential decrease of whole-body activity with half-lives of 101 and 232 min. Tracer elimination was mainly renal, with 92% and 98% of activity counted in urine in the first 20 h. Kidney, liver, spleen, and bone marrow activity uptake was observed in all patients. Tumor was not visualized in the first 3 patients but could be localized by tomoscintigraphy in the pancreas head region of patient 4. In vitro tissue analysis showed high expression of NT receptor in the tumor of patient 4, correlated with the highest tumor radioactivity uptake and the highest tumor-to-fat radioactivity ratio. In vitro receptor expression was also positive in a second patient having a tumor characterized by very low cellularity; however, the remaining 2 tumors lacked NT receptor expression. CONCLUSION: Injection of (99m)Tc-NT-XI was well tolerated. The in vivo tumor uptake appeared specific as it was observed in the 1 patient with a pancreatic tumor that expressed high amounts of NT receptor. The results are compatible with preclinical animal results and in favor of further development of radiolabeled NT analogs for diagnosis or therapy of cancer.

Adenocarcinoma↗

PubMed2002

Acrylic acid grafting and collagen immobilization on poly(ethylene terephthalate) surfaces for adherence and growth of human bladder smooth muscle cells.

In tissue engineering, degradable or non-degradable polymer matrices can act as cell-carrier-scaffolds. Cell adhesion and growth on these scaffolds can be promoted by immobilizing extracellular matrix proteins. Therefore, in this study, polymer poly(ethylene terephthalate) (PET) films were surface modified by graft polymerization of acrylic acid, to subsequently allow collagen (types I and III) immobilization and human smooth muscle cell expansion. The surfaces of PET were activated by plasma, followed by acrylic acid graft polymerization, resulting in covalently bound brushes, containing an average of either 0.22+/-0.1 or 5.93+/-0.87 microg/cm2 of poly(acrylic acid) (PAA). Subsequent electrostatic adsorption of collagen gave a surface concentration of 4.96 and 17.2 microg/cm2, respectively, as determined using radiolabelled 125I collagen. Both PET films grafted with 0.22 microg/cm2 of PAA with or without adsorbed collagen were apt for smooth muscle cell adhesion and proliferation. However, films grafted with 5.93 microg/cm2 were not. PAA-grafted PET films, onto which serum proteins of the culture medium adsorbed spontaneously, proved to be better matrices than films on which collagen has been immobilized. It, therefore, can be speculated that other serum proteins are more important than collagen for the human smooth muscle cell adhesion and growth on surface-modified polymer matrices.

Acrylic Resins↗