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Lundqvist, Hans
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Publications (10 of 41) Show all publications
Mortensen, A., Spiegelberg, D., Haylock, A.-K., Lundqvist, H. & Nestor, M. (2018). Preclinical evaluation of a novel engineered recombinant human anti-CD44v6 antibody for potential use in radio-immunotherapy. International Journal of Oncology, 52(6), 1875-1885
Open this publication in new window or tab >>Preclinical evaluation of a novel engineered recombinant human anti-CD44v6 antibody for potential use in radio-immunotherapy
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2018 (English)In: International Journal of Oncology, ISSN 1019-6439, Vol. 52, no 6, p. 1875-1885Article in journal (Refereed) Published
Abstract [en]

CD44v6 is overexpressed in a variety of cancers, rendering it a promising target for radio-immunotherapy (RIT). In this study, we have characterized a novel engineered recombinant monoclonal anti-CD44v6 antibody, AbN44v6, and assessed its potential for use in RIT using either Lu-177 or I-131 as therapeutic radionuclides. In vitro affinity and specificity assays characterized the binding of the antibody labeled with Lu-177, I-125 or I-131. The therapeutic effects of Lu-177-AbN44v6 and I-131-AbN44v6 were investigated using two in vitro 3D tumor models with different CD44v6 expression. Finally, the normal tissue biodistribution and dosimetry for Lu-177-AbN44v6 and I-125-AbN44v6/I-131-AbN44v6 were assessed in vivo using a mouse model. All AbN44v6 radioconjugates demonstrated CD44v6-specific binding in vitro. In the in vitro 3D tumor models, dose-dependent therapeutic effects were observed with both Lu-177-AbN44v6 and I-131-AbN44v6, with a greater significant therapeutic effect observed on the cells with a higher CD44v6 expression. Biodistribution experiments demonstrated a greater uptake of Lu-177-AbN44v6 in the liver, spleen and bone, compared to I-125-AbN44v6, whereas I-125-AbN44v6 demonstrated a longer circulation time. In dosimetric calculations, the critical organs for Lu-177-AbN44v6 were the liver and spleen, whereas the kidneys and red marrow were considered the critical organs for I-131-AbN44v6. The effective dose was in the order of 0.1 mSv/MBq for both labels. In conclusion, AbN44v6 bound specifically and with high affinity to CD44v6. Furthermore, in vitro RIT demonstrated growth inhibition in a CD44v6-specific activity-dependent manner for both radioconjugates, demonstrating that both Lu-177-AbN44v6 and I-131-AbN44v6 may be promising RIT candidates. Furthermore, biodistribution and dosimetric analysis supported the applicability of both conjugates for RIT. The CD44v6-specific therapeutic effects observed with radiolabeled AbN44v6 in the 3D tumor models in vitro, combined with the beneficial dosimetry in vivo, render AbN44v6 a potential candidate for RIT.

Place, publisher, year, edition, pages
SPANDIDOS PUBL LTD, 2018
Keywords
radio-immunotherapy, 3D tumor models, dosimetry, biodistribution, Lu-177, I-131
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-356443 (URN)10.3892/ijo.2018.4364 (DOI)000432241200010 ()29658563 (PubMedID)
Funder
Swedish Research CouncilSwedish Cancer Society
Available from: 2018-07-31 Created: 2018-07-31 Last updated: 2018-07-31Bibliographically approved
Garske, U., Sandström, M., Fröss-Baron, K., Lundin, L., Hellman, P., Welin, S., . . . Granberg, D. (2018). Prospective observational study of 177Lu-DOTA-octreotate therapy in 200 patients with advanced metastasized neuroendocrine tumours (NETs): feasibility and impact of a dosimetry-guided study protocol on outcome and toxicity. European Journal of Nuclear Medicine and Molecular Imaging, 45(6), 970-988
Open this publication in new window or tab >>Prospective observational study of 177Lu-DOTA-octreotate therapy in 200 patients with advanced metastasized neuroendocrine tumours (NETs): feasibility and impact of a dosimetry-guided study protocol on outcome and toxicity
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2018 (English)In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 45, no 6, p. 970-988Article in journal (Refereed) Published
Abstract [en]

PURPOSE: Peptide receptor radionuclide therapy in patients with neuroendocrine tumours has yielded promising results. This prospective study investigated the feasibility of dosimetry of the kidneys and bone marrow during therapy and its impact on efficacy and outcome.

METHODS: Lu-DOTA-octreotate with co-infusion of a mixed amino acid solution, and cycles were repeated until the absorbed dose to the kidneys reached 23 Gy or there were other reasons for stopping therapy. The Ki-67 index was ≤2% in 47 patients (23.5%), 3-20% in 121 (60.5%) and >20% in 16 (8%).

RESULTS: In 123 patients (61.5%) the absorbed dose to the kidneys reached 23 Gy with three to nine cycles during first-line therapy; in no patient was a dose to the bone marrow of 2 Gy reached. The best responses (according to RECIST 1.1) were a complete response (CR) in 1 patient (0.5%), a partial response (PR) in 47 (23.5%), stable disease (SD) in 135 (67.5%) and progressive disease (PD) in 7 (3.5%). Median progression-free survival was 27 months (95% CI 22-30 months) in all patients, 33 months in those in whom the absorbed dose to the kidneys reached 23 Gy and 15 months in those in whom it did not. Median overall survival (OS) was 43 months (95% CI 39-53 months) in all patients, 54 months in those in whom the absorbed dose to the kidneys reached 23 Gy and 25 months in those in whom it did not. Median OS was 60 months in patients with a best response of PR or CR, 42 months in those with SD and 16 months in those with PD. Three patients (1.5%) developed acute leukaemia, 1 patient (0.5%) chronic leukaemia (unconfirmed) and 30 patients (15%) grade 3 or 4 bone marrow toxicity. Eight patients (4%) developed grade 2 kidney toxicity and one patient (0.5%) grade 4 kidney toxicity.

CONCLUSIONS: Lu-DOTA-octreotate is feasible. Patients in whom the absorbed dose to the kidneys reached 23 Gy had a longer OS than those in whom it did not. Patients with CR/PR had a longer OS than those with SD. Bone marrow dosimetry did not predict toxicity.

Keywords
177Lu-DOTA-octreotate, Dosimetry, Neuroendocrine tumour, Outcome, PRRT, Toxicity
National Category
Radiology, Nuclear Medicine and Medical Imaging Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-346995 (URN)10.1007/s00259-018-3945-z (DOI)000430832400010 ()29497803 (PubMedID)
Available from: 2018-03-23 Created: 2018-03-23 Last updated: 2018-08-02Bibliographically approved
Velikyan, I., Sundin, A., Sörensen, J., Lubberink, M., Sandström, M., Garske-Román, U., . . . Eriksson, B. (2014). Quantitative and Qualitative Intrapatient Comparison of 68Ga-DOTATOC and 68Ga-DOTATATE: Net Uptake Rate for Accurate Quantification.. Journal of Nuclear Medicine, 55(2), 204-10
Open this publication in new window or tab >>Quantitative and Qualitative Intrapatient Comparison of 68Ga-DOTATOC and 68Ga-DOTATATE: Net Uptake Rate for Accurate Quantification.
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2014 (English)In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 55, no 2, p. 204-10Article in journal (Refereed) Published
Abstract [en]

UNLABELLED: Quantitative imaging and dosimetry are crucial for individualized treatment during peptide receptor radionuclide therapy (PRRT). (177)Lu-DOTATATE and (68)Ga-DOTATOC/(68)Ga-DOTATATE are used, respectively, for PRRT and PET examinations targeting somatostatin receptors (SSTRs) in patients affected by neuroendocrine tumors. The aim of the study was to quantitatively and qualitatively compare the performance of (68)Ga-DOTATOC and (68)Ga-DOTATATE in the context of subsequent PRRT with (177)Lu-DOTATATE under standardized conditions in the same patient as well as to investigate the sufficiency of standardized uptake value (SUV) for estimation of SSTR expression.

METHODS: Ten patients with metastatic neuroendocrine tumors underwent one 45-min dynamic and 3 whole-body PET/CT examinations at 1, 2, and 3 h after injection with both tracers. The number of detected lesions, SUVs in lesions and normal tissue, total functional tumor volume, and SSTR volume (functional tumor volume multiplied by mean SUV) were investigated for each time point. Net uptake rate (Ki) was calculated according to the Patlak method for 3 tumors per patient.

RESULTS: There were no significant differences in lesion count, lesion SUV, Ki, functional tumor volume, or SSTR volume between (68)Ga-DOTATOC and (68)Ga-DOTATATE at any time point. The detection rate was similar, although with differences for single lesions in occasional patients. For healthy organs, marginally higher uptake of (68)Ga-DOTATATE was observed in kidneys, bone marrow, and liver at 1 h. (68)Ga-DOTATOC uptake was higher in mediastinal blood pool at the 1-h time point (P = 0.018). The tumor-to-liver ratio was marginally higher for (68)Ga-DOTATOC at the 3-h time point (P = 0.037). Blood clearance was fast and similar for both tracers. SUV did not correlate with Ki linearly and achieved saturation for a Ki of greater than 0.2 mL/cm(3)/min, corresponding to an SUV of more than 25.

CONCLUSION: (68)Ga-DOTATOC and (68)Ga-DOTATATE are suited equally well for staging and patient selection for PRRT with (177)Lu-DOTATATE. However, the slight difference in the healthy organ distribution and excretion may render (68)Ga-DOTATATE preferable. SUV did not correlate linearly with Ki and thus may not reflect the SSTR density accurately at its higher values, whereas Ki might be the outcome measure of choice for quantification of SSTR density and assessment of treatment outcome.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-219605 (URN)10.2967/jnumed.113.126177 (DOI)000330926200034 ()24379222 (PubMedID)
Available from: 2014-03-04 Created: 2014-03-04 Last updated: 2017-12-05Bibliographically approved
Sandström, M., Garske-Roman, U., Granberg, D., Eriksson, B., Sundin, A., Lundqvist, H. & Lubberink, M. (2013). Biological effective doses in 300 patients undergoing therapy with Lu-177-octreotate. Paper presented at Annual Congress of the European-Association-of-Nuclear-Medicine (EANM); OCT 19-23, 2013; Lyon, FRANCE. European Journal of Nuclear Medicine and Molecular Imaging, 40(Suppl. 2), S201-S201
Open this publication in new window or tab >>Biological effective doses in 300 patients undergoing therapy with Lu-177-octreotate
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2013 (English)In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 40, no Suppl. 2, p. S201-S201Article in journal, Meeting abstract (Other academic) Published
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-211598 (URN)000325853400349 ()
Conference
Annual Congress of the European-Association-of-Nuclear-Medicine (EANM); OCT 19-23, 2013; Lyon, FRANCE
Available from: 2013-12-03 Created: 2013-11-27 Last updated: 2017-12-06Bibliographically approved
Sandström, M., Velikyan, I., Garske-Roman, U., Sörensen, J., Eriksson, B., Granberg, D., . . . Lubberink, M. (2013). Comparative Biodistribution and Radiation Dosimetry of Ga-68-DOTATOC and Ga-68-DOTATATE in Patients with Neuroendocrine Tumors. Journal of Nuclear Medicine, 54(10), 1755-1759
Open this publication in new window or tab >>Comparative Biodistribution and Radiation Dosimetry of Ga-68-DOTATOC and Ga-68-DOTATATE in Patients with Neuroendocrine Tumors
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2013 (English)In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 54, no 10, p. 1755-1759Article in journal (Refereed) Published
Abstract [en]

Ga-68-DOTATOC and Ga-68-DOTATATE are 2 radiolabeled somatostatin analogs for in vivo diagnosis of neuroendocrine tumors with PET. The aim of the present work was to measure their comparative biodistribution and radiation dosimetry. Methods: Ten patients diagnosed with neuroendocrine tumors were included. Each patient underwent a 45-min dynamic and 3 whole-body PET/CT scans at 1, 2, and 3 h after injection of each tracer on consecutive days. Absorbed doses were calculated using OLINDA/EXM 1.1. Results: Data from 9 patients could be included in the analysis. Of the major organs, the highest uptake at 1, 2, and 3 h after injection was observed in the spleen, followed by kidneys and liver. For both tracers, the highest absorbed organ doses were seen in the spleen and urinary bladder wall, followed by kidney, adrenals, and liver. The absorbed doses to the liver and gallbladder wall were slightly but significantly higher for Ga-68-DOTATATE. The total effective dose was 0.021 +/- 0.003 mSv/MBq for both tracers. Conclusion: The effective dose for a typical 100-MBq administration of Ga-68-DOTATATE and Ga-68-DOTATOC is 2.1 mSv for both tracers. Therefore, from a radiation dosimetry point of view, there is no preference for either tracer for PET/CT evaluation of somatostatin receptor-expressing tumors.

Keywords
biodistribution, dosimetry, Ga-68-DOTATATE, Ga-68-DOTATOC, neuroendocrine tumors
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-210211 (URN)10.2967/jnumed.113.120600 (DOI)000325341300015 ()
Available from: 2013-11-04 Created: 2013-11-04 Last updated: 2017-12-06Bibliographically approved
Enger, S. A., Giusti, V., Fortin, M.-A., Lundqvist, H. & af Rosenschold, P. M. (2013). Dosimetry for gadolinium neutron capture therapy (GdNCT). Radiation Measurements, 59, 233-240
Open this publication in new window or tab >>Dosimetry for gadolinium neutron capture therapy (GdNCT)
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2013 (English)In: Radiation Measurements, ISSN 1350-4487, E-ISSN 1879-0925, Vol. 59, p. 233-240Article in journal (Refereed) Published
Abstract [en]

Background:

Gadolinium (Gd) neutron capture therapy (GdNCT) is based on a neutron capture reaction (NCR) that involves emission of both short and long range products. The aim of this study was to investigate both the microscopic and macroscopic contributions of the absorbed dose involved in GdNCT.

Methods:

Cylindrical containers with diameters 1-30 mm filled with a solution of Gd were irradiated with epithermal neutrons. The background neutron dose as well as the prompt gamma dose has been calculated and measured by means of film dosimetry for the largest cylinder. Monte Carlo codes MCNP5(b) and GEANT4 have been utilized for calculation the absorbed dose.

Results and discussion:

Results from the film dosimetry are in agreement with the calculations for high doses while for low doses the measured values are higher than the calculated results. For the largest cylinder, the prompt gamma dose from GdNCR neutron is at least five times higher than the background dose. For a cell cluster model, in the first 0.1 mm the major contribution to the absorbed dose is from IC electrons. If Gd atoms were homogeneously distributed in the nuclei of all tumour cells, capture events between neutron and Gd atoms close to DNA could kill the tumour cells and give cross-fire dose from IC electrons to the cells located in the 0.1 mm range.

Conclusions:

For a correct GdNCT dosimetry both microscopic part of the dose delivered by short-range low energy electrons and macroscopic part delivered by the prompt gamma should be considered.

Keywords
Gadolinium neutron capture therapy, Tumour therapy, Gadolinium nanoparticle
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-218606 (URN)10.1016/j.radmeas.2013.05.009 (DOI)000329421700037 ()
Available from: 2014-02-13 Created: 2014-02-13 Last updated: 2017-12-06Bibliographically approved
Sandström, M., Garske-Román, U., Granberg, D., Johansson, S., Widström, C., Eriksson, B., . . . Lubberink, M. (2013). Individualized dosimetry of kidney and bone marrow in patients undergoing 177Lu-DOTA-octreotate treatment. Journal of Nuclear Medicine, 54(1), 33-41
Open this publication in new window or tab >>Individualized dosimetry of kidney and bone marrow in patients undergoing 177Lu-DOTA-octreotate treatment
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2013 (English)In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 54, no 1, p. 33-41Article in journal (Refereed) Published
Abstract [en]

The organs at risk in radionuclide therapy with 177Lu-octreotate are the bone marrow and the kidneys. The primary aim of this study was to develop an individualized dosimetry protocol for the bone marrow. The secondary aim was to identify those patients, undergoing fractionated therapy with 7.4 GBq/cycle, who first reached an accumulated dose of either 2 Gy to the bone marrow or 23 Gy to the kidneys. Methods: Two hundred patients with metastatic neuroendocrine tumors with high somatostatin receptor expression were included. After the administration of 7.4 GBq of 177Lu-octreotate, blood samples were drawn 6 times within the first 24 h. In 50 patients, additional blood samples were obtained at 96 and 168 h. Moreover, urine was collected from 30 patients during the first 24 h. Planar whole-body and SPECT/CT images over the abdomen were acquired at 24, 96, and 168 h after the infusion. Calculation of the absorbed radiation dose to the bone marrow was based on blood and urinary activity curves combined with organ-based analysis of the whole-body images. The absorbed dose to the kidney was calculated from the pharmacokinetic data obtained from SPECT/CT. Results: For a single cycle of 7.4 GBq, the absorbed dose to the bone marrow and the kidney ranged from 0.05 to 0.4 Gy and from 2 to 10 Gy, respectively. In 197 of 200 patients, the kidneys accumulated an absorbed dose of 23 Gy before the bone marrow reached 2 Gy. Between 2 and 10 cycles of 177Lu-octreotate could be administered before the upper dose limit for the individual patient was reached. Conclusion: A method based on repeated whole-body imaging in combination with blood and urinary activity data over time was developed to determine the absorbed dose to the bone marrow. The dose-limiting organ was the kidney in 197 of 200 patients. In 50% of the patients, more than 4 cycles of 7.4 GBq of 177Lu-octreotate could be administered, whereas 20% of the subjects were treated with fewer than 4 cycles. Individualized absorbed dose calculation is essential to optimize the therapy.

Keywords
177Lu-DOTA-octreotate, Bone marrow, Dosimetry, Individualized, Kidney
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-183412 (URN)10.2967/jnumed.112.107524 (DOI)000313606800027 ()
Available from: 2012-10-25 Created: 2012-10-25 Last updated: 2017-12-07Bibliographically approved
Orlova, A., Jonsson, A., Rosik, D., Lundqvist, H., Lindborg, M., Abrahmsen, L., . . . Tolmachev, V. (2013). Site-Specific Radiometal Labeling and Improved Biodistribution Using ABY-027, A Novel HER2-Targeting Affibody Molecule-Albumin-Binding Domain Fusion Protein. Journal of Nuclear Medicine, 54(6), 961-968
Open this publication in new window or tab >>Site-Specific Radiometal Labeling and Improved Biodistribution Using ABY-027, A Novel HER2-Targeting Affibody Molecule-Albumin-Binding Domain Fusion Protein
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2013 (English)In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 54, no 6, p. 961-968Article in journal (Refereed) Published
Abstract [en]

Because of their better penetration, smaller targeting proteins may be superior to antibodies for radioimmunotherapy of solid tumors. Therefore, Affibody molecules (6.5 kDa) have a potential for being suitable as targeted moiety for radiolabeled therapeutic proteins. Previous studies have demonstrated that a fusion of an Affibody molecule with an albumin-binding domain (ABD) provides a strong noncovalent binding to albumin in vivo. This strong noncovalent binding can be used for reduction of the renal uptake of the Affibody molecule while maintaining a size smaller than that of an antibody, which is important when using residualizing radionuclide labels conjugated to Affibody molecules. The goal of this study was to design and evaluate a new targeting Affibody–ABD fusion protein with improved biodistribution properties for radionuclide therapy.

Methods:

A novel Affibody-based construct, ZHER2:2891-ABD035-DOTA (ABY-027), was created by fusion of the reengineered HER2-binding Affibody molecule ZHER2:2891 to the N terminus of the high-affinity ABD035, and a maleimido-derivative of DOTA was conjugated at the C terminus of the construct. Binding and processing of 177Lu-ABY-027 by HER2-expressing cells were evaluated in vitro. Targeting of HER2-expressing SKOV-3 xenografts was evaluated in BALB/C nu/nu mice and compared with targeting of previously reported ABD-(ZHER2:342)2.

Results:

The binding affinity (dissociation constant) of ABY-027 to HER2 (74 pM) was the same as for the parental ZHER2:2891 (76 pM). ABY-027 was stably labeled with 177Lu and 111In with preserved specific binding to HER2-expressing cells in vitro. In vivo receptor saturation experiments demonstrated that targeting of SKOV-3 xenografts in BALB/C nu/nu mice was HER2-specific. 177Lu-ABY-027 demonstrated substantially (2- to 3-fold) lower renal and hepatic uptake than previously assessed HER2-specific Affibody-based albumin-binding agents. Tumor uptake of radiolabeled ABY-027 at 48 h after injection was 2-fold higher than that for previously reported ABD-(ZHER2:342)2.

Conclusion:

An optimized molecular design of an ABD fusion protein resulted in an Affibody molecule construct with better properties for therapy. Fully preserved in vivo targeting of the fusion protein was shown in xenografted mice. Site-specific coupling of DOTA provides a uniform conjugate and creates the potential for labeling with a broad range of therapeutic radionuclides. The biodistribution of 177Lu-ABY-027 in a murine model suggests it is more suitable for therapy than alternative approaches.

National Category
Basic Medicine
Identifiers
urn:nbn:se:uu:diva-203051 (URN)10.2967/jnumed.112.110700 (DOI)000319811400020 ()23528382 (PubMedID)
Available from: 2013-07-02 Created: 2013-07-02 Last updated: 2018-01-11Bibliographically approved
Lattuada, M., Maripuu, E., Hård af Segerstad, C., Lundqvist, H. & Hedenstierna, G. (2012). Evaluating abdominal oedema during experimental sepsis using an isotope technique. Clinical Physiology and Functional Imaging, 32(3), 197-204
Open this publication in new window or tab >>Evaluating abdominal oedema during experimental sepsis using an isotope technique
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2012 (English)In: Clinical Physiology and Functional Imaging, ISSN 1475-0961, E-ISSN 1475-097X, Vol. 32, no 3, p. 197-204Article in journal (Refereed) Published
Abstract [en]

Purpose: Abdominal oedema is common in sepsis. A technique for the study of such oedema may guide in the fluid regime of these patients.

Procedures: We modified a double-isotope technique to evaluate abdominal organ oedema and fluid extravasation in 24 healthy or endotoxin-exposed (septic) piglets. Two different markers were used: red blood cells (RBC) labelled with Technetium99m (99mTc) and Transferrin labelled with Indium111 (111In). Images were acquired on a dual-head gamma camera. Microscopic evaluation of tissue biopsies was performed to compare data with the isotope technique.

Results: No 99mTc activity was measured in the plasma fraction in blood sampled after labelling. Similarly, after molecular size gel chromatography, 111In activity was exclusively found in the high molecular fraction of the plasma. Extravasation of transferrin, indicating the degree of abdominal oedema, was 4 06 times higher in the LPS group compared to the healthy controls (P< 0 0001). Abdominal free fluid, studied in 3 animals, had as high 111In activity as in plasma, but no 99mTc activity. Intestinal lymphatic vessel size was higher in LPS (3 7 +/- 1 1 lm) compared to control animals (0 6 + 0 2 lm; P< 0 001) and oedema correlated to villus diameter (R 2 = 0 918) and lymphatic diameter (R 2 = 0 758). A correlation between a normalized index of oedema formation (NI) and intra-abdominal pressure (IAP) was also found: NI = 0 46* IAP) 3 3 (R2 = 0 56).

Conclusions: The technique enables almost continuous recording of abdominal oedema formation and may be a valuable tool in experimental research, with the potential to be applied in the clinic.

Keywords
abdomen, double indicator, gamma camera, microscopy, oedema
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-173971 (URN)10.1111/j.1475-097X.2011.01077.x (DOI)000302545300006 ()
Available from: 2012-05-14 Created: 2012-05-09 Last updated: 2017-12-07Bibliographically approved
Gedda, L., Fondell, A., Lundqvist, H., Park, J. & Edwards, K. (2012). Experimental radionuclide therapy of HER2-expressing xenografts using two-step targeting Nuclisome-particles. Journal of Nuclear Medicine, 53(3), 480-487
Open this publication in new window or tab >>Experimental radionuclide therapy of HER2-expressing xenografts using two-step targeting Nuclisome-particles
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2012 (English)In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 53, no 3, p. 480-487Article in journal (Refereed) Published
Abstract [en]

The therapeutic potential of Auger-electron emitting radionuclides is strongly dependent on their close vicinity to DNA, since the energy deposition is mainly localized within a few cubic nanometers around the site of decay. Thus, apart from specificity, successful tumor therapy relies on a nuclear delivery strategy. We recently presented a two-step targeting strategy to transport Auger-electron-emitting radionuclides into the cell nucleus by means of nuclide-filled liposomes (Nuclisome particles), that is, polyethylene glycol-stabilized, tumor-cell-targeting liposomes loaded with (125)I-labeled anthracyclines. In the present study, the survival of mice intraperitoneally inoculated with human HER2-expressing SKOV-3 tumor cells and treated with HER2-targeting Nuclisome particles was studied.

METHODS:

BALB/c nu/nu mice were inoculated with 10(7) SKOV-3 cells intraperitoneally and thereafter directly injected with Nuclisome particles with increasing specific radioactivity. Groups of 10-12 mice were treated with 0.01 MBq/mouse up to 2 MBq/mouse, and survival was monitored and compared with that in control groups (n = 33). Organs were analyzed for HER2 expression and radiotoxic effects histologically. Absorbed doses were estimated using dose factors from the online Radiation Dose Assessment Resource model.

RESULTS:

The results showed a clear correlation between administered radioactive dose and survival. No such dose-dependent survival was observed for mice treated with Nuclisome particles lacking HER2-targeting ability. With HER2-targeting Nuclisome particles, a significant increase in survival, compared with that of untreated control mice, could already be seen at an administered activity of 0.1 MBq/mouse (P = 0.0301). At the highest activity administered, 2 MBq/mouse (P < 0.0001), 70% of the mice survived the study and most were tumor-free. Neither macroscopic nor microscopic radiotoxic side effects were observed. Dosimetric calculations, assuming nonreceptor targeting, revealed that the radioactive doses to normal tissues were low.

CONCLUSION:

Taken together the results show that with successful targeting to the tumor-cell nucleus it is possible to obtain a therapeutic effect from Auger-electron-emitting radionuclides administered at radioactive doses low enough to spare normal tissue from radiotoxic side effects.

National Category
Other Basic Medicine
Identifiers
urn:nbn:se:uu:diva-158992 (URN)10.2967/jnumed.111.096891 (DOI)000301194300046 ()22323773 (PubMedID)
Available from: 2011-09-20 Created: 2011-09-20 Last updated: 2018-01-12Bibliographically approved
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