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Aspects of Tumour Targeting: Preclinical Studies on Human Malignant Cells in vitro
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Exclusive eradication of tumour cells causing minimal damage to healthy tissue, a concept referred to as targeting, is an interesting approach to improve the outcome for patients afflicted with cancer.

The general aim of this thesis was to highlighten aspects that could be of importance in developing novel treatment regimens based on specific targeting of tumour cells. Two variants of targeting strategies, boron neutron capture therapy (BNCT) and platelet-derived growth factor receptor (PDGFR) tumour targeting were studied in vitro.

In BNCT, the ability of boron-10, 10B, to capture neutrons is utilized. The capture reaction initiate emission of high linear energy transfer (LET) particles which exerts potential damaging effects on exposed cells. A preferential accumulation of at least 10 μg 10B/g tumour tissue is suggested to be required for effective clinical outcome. Here, the accumulation of boronophenylalanine, BPA, was investigated in human glioma, synovial sarcoma, fibroblast and monocytoid cells in vitro. For the purpose of quick and effective separation of extracellular and cell-associated boron, a rapid cell filtration method was developed. Inductively coupled plasma atomic emission spectroscopy, ICP-AES, was used to analyse the amount of boron associated to the cells.

Over-expression of PDGFRs may render the possibility to target certain tumours using PDGF-based conjugates for a specific delivery of cytotoxic agents. PDGF-AA was conjugated to dextran of two different sizes, 10 and 40 kDa, and compared with 125I-radiolabelled PDGF-AA regarding accumulation, retention and localisation in human glioma cells in vitro.

A boron concentration of >10 μg 10B/g tumour tissue was found in all human cell lines studied. For the two glioma cell lines, the results extend differences between the two although originating from the same human tumour material. Since fibroblasts and monocytoid cells, here used to represent normal cells, accumulated boron at a clinically relevant amount one may have to consider the role of these cells in/at the tumour site during treatment. Regarding results for the human synovial sarcoma cells, further investigations may state the potential of BNCT as a treatment modality and explore the possibilities of a directed delivery of boron-containing substances to receptors specifically expressed in this malignancy.

PDGF-AA-based dextran conjugates, preferentially 10 kDa dextran conjugates, showed in vitro properties that were superior to radiolabelled unconjugated PDGF-AA. A prolonged retention time was observed for the conjugates. Radiolabelled PDGF-AA was mainly determined to be located intracellular but the localisation, internalised or membrane-associated, of radiolabelled conjugates seemed to be dependent on the composition of the conjugate. It is of interest to explore the potential of dextran conjugates carrying toxic substances for therapeutic purpose.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press , 2009. , 80 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1118
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-18471ISBN: 978-91-7393-649-1 (print)OAI: oai:DiVA.org:liu-18471DiVA: diva2:219704
Public defence
2009-06-04, Aulan, Hälsans Hus, Campus US, Linköpings Universitet, Linköping, 09:00 (English)
Opponent
Supervisors
Available from: 2009-05-28 Created: 2009-05-28 Last updated: 2009-06-22Bibliographically approved
List of papers
1. Accumulation of boron in human malignant glioma cells in vitro is cell type dependent
Open this publication in new window or tab >>Accumulation of boron in human malignant glioma cells in vitro is cell type dependent
Show others...
2004 (English)In: Journal of Neuro-Oncology, ISSN 0167-594X, E-ISSN 1573-7373, Vol. 68, no 3, 199-205 p.Article in journal (Refereed) Published
Abstract [en]

It has been shown that human malignant glioma tumours consist of several subpopulations of tumour cells. Due to heterogeneity and different degrees of vascularisation cell subpopulations possess varying resistance to chemo- or radiation therapy. Therefore, therapy is dependent on the ability to specifically target a tumour cell. Boron neutron capture therapy (BNCT) is a bimodal method, in radiation therapy, taking advantage of the ability of the stable isotope boron-10 to capture neutrons. It results in disintegration products depositing large amounts of energy within a short length, approximately one cell diameter. Thereby, selective irradiation of a target cell may be accomplished if a sufficient amount of boron has been accumulated and hence the cell-associated boron concentration is of critical importance. The accumulation of boron, boronophenylalanine (BPA), was investigated in two human glioma cell subpopulations and a human fibroblast cell line in vitro. The cells were incubated at low boron concentrations (0-5 microg B/ml). Oil filtration was then used for separation of extracellular and cell-associated boron. Inductively coupled plasma atomic emission spectroscopy (ICP-AES) was used for boron determination. Significant (P < 0.05) differences in accumulation ratio (relation between cell-associated and extracellular boron concentration) between human malignant glioma cell lines were found. Human fibroblasts, used to represent normal cells, showed a growth-dependent uptake and a lower accumulation ratio than the glioma cells. Our findings indicate that BPA concentration, incubation time and differences in boron uptake between cell subpopulations should be considered in BNCT.

Keyword
BNCT, BPA, fibroblasts, glioblastoma multiforme, glioma cell lines, in vitro
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-18467 (URN)10.1023/B:NEON.0000033489.54011.6b (DOI)15332322 (PubMedID)
Available from: 2009-05-28 Created: 2009-05-28 Last updated: 2017-12-13Bibliographically approved
2. Accumulation of 10B in human synovial sarcoma cells in vitro for possible use in BNCT
Open this publication in new window or tab >>Accumulation of 10B in human synovial sarcoma cells in vitro for possible use in BNCT
(English)Manuscript (Other academic)
Abstract [en]

Synovial sarcoma is a distinct tumour with unique promise for targeted therapy. Due to the location and characteristics, boron neutron capture therapy (BNCT) might be an interesting alternative treatment regimen. The binary method utilizes the ionizing effects of high energy short-ranged fission particles produced after the capturing of neutrons by stable 10B. This study reports results regarding the accumulation of 10B administered as boronophenylalanine (BPA) in a human synovial sarcoma cell line (4SS) in vitro. 4SS cells were incubated in BPAcontaining cell culture medium and cell-associated boron was analysed using inductively coupled plasma atomic emission spectroscopy (ICP-AES). The results show that 4SS cells accumulate boron in a clinical relevant concentration range. Further investigations may state the potential of BNCT as a treatment modality for synovial sarcomas and explore the possibilities of a directed delivery of boron-containing substances to receptors specifically expressed in this malignancy.

Keyword
Synovial sarcoma, boron neutron capture therapy, BNCT, boronophenylalanine, BPA, targeting, 4SS, in vitro, cell culture, cell-associated boron
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-18468 (URN)
Available from: 2009-05-28 Created: 2009-05-28 Last updated: 2010-01-14Bibliographically approved
3. Undifferentiated monocytoid U937-1 cells accumulate boron-10 after administration of BPA in vitro
Open this publication in new window or tab >>Undifferentiated monocytoid U937-1 cells accumulate boron-10 after administration of BPA in vitro
(English)Manuscript (Other academic)
Abstract [en]

A tumour influences it’s surrounding and is at the same time influenced by surrounding cells. It is established that a majority of malignant tumours are infiltrated by macrophages, so called tumour-associated macrophages (TAMs) and that this infiltration is associated with poor prognosis. The role of TAMs is not completely revealed but evidence has emerged for a symbiotic relationship between tumour cells and TAMs. In this context, one may consider the importance of TAMs during tumour eradication. In this study, undifferentiated human monocytoid U937-1 cells were used as a model of normal monocytes and analysed regarding accumulation of boronophenylalanine (BPA) in vitro. BPA is a compound used extensively in vitro, in vivo and in clinical trials for boron neutron capture therapy (BNCT). The high energy ionizing radiation utilized in the BNCT process may also affect TAMs; directly if TAMs accumulate boron or through bystander effects initiated by the irradiation. Undifferentiated cells were incubated in BPA-containing cell culture medium at boron concentrations of 0-5 μg 10B/ml. A rapid oil filtration method was used for separation of extracellular and cellassociated boron. Boron content was analysed using inductively coupled plasma atomic emission spectroscopy (ICP-AES). It was shown that undifferentiated U937-1 cells accumulate boron in a clinical relevant concentration range. Further investigations are needed to reveal the role of TAMs in tumours and eventual interaction during the treatment, here specifically when utilizing BNCT.

Keyword
Monocyte, macrophage, U937-1, boronophenylalanine, BPA, in vitro, accumulation, ICP-AES, tumour-associated macrophages, TAMs, bystander effect
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-18469 (URN)
Available from: 2009-05-28 Created: 2009-05-28 Last updated: 2010-01-14Bibliographically approved
4. Targeting malignant glioma cells in vitro using platelet-derived growth factor AA-based conjugates
Open this publication in new window or tab >>Targeting malignant glioma cells in vitro using platelet-derived growth factor AA-based conjugates
2009 (English)In: Journal of drug targeting, ISSN 1029-2330, 1-10 p.Article in journal (Refereed) Published
Abstract [en]

Glioblastoma multiforme (GBM) is an unusually aggressive brain tumor; it is also highly heterogeneous. Poor prognosis and a median survival of less than 1 year, using conventional treatment, calls for development of new treatment strategies. Overexpression and/or amplification of platelet-derived growth factor alpha receptors (PDGFalphaRs) in GBM might act as potential targets for a novel therapeutic approach. In this study, conjugates based on PDGFAA-ligand and dextran, of different sizes (10 and 40 kDa dextran), were prepared and investigated regarding targeting properties in vitro. Three human malignant glioma cell lines, U343MGa31L, U343MGaCl2:6, and U563MG, were used because of their previously reported differences in receptor expression and behavior. PDGFAA-based 10 kDa dextran iodine-125 radiolabeled conjugates showed the most favorable properties according to results achieved in accumulation, retention, and localization of cell-associated radioactivity. In comparison with dextran-(125)I-tyrosine delivered radioactivity, the PDGFAA-based dextran conjugates confirm the potential of receptor targeting.

Keyword
Conjugate, dextran, glioblastoma multiforme, PDGFAA, PDGF receptors, targeting
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-18470 (URN)10.1080/10611860902718698 (DOI)19255898 (PubMedID)
Available from: 2009-05-28 Created: 2009-05-28 Last updated: 2009-05-28Bibliographically approved

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Dahlström Wester, Maria

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