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In vitro evaluation and biodistribution of HER2-targeted liposomes loaded with an 125I-labelled DNA-intercalator
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry, Physical Chemistry.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry, Physical Chemistry.
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2011 (English)In: Journal of drug targeting (Print), ISSN 1061-186X, E-ISSN 1029-2330, Vol. 19, no 9, 846-855 p.Article in journal (Refereed) Published
Abstract [en]

Background: Increasing attention is currently focussed on the issue of finding strategies for the delivery of Auger-electron emitting radionuclides into tumour cell nuclei. Nuclear localisation is a prerequisite for these radionuclides, since their radiotoxic properties are functional only in close vicinity to DNA.

Purpose: In this study we investigated tumour-cell uptake and cell killing ability in vitro, as well as in vivo biodistribution of an 125I-labelled anthracycline derivative administered by means of HER2-targeted liposomes.

Methods: Anthracycline derivative Comp1 was radiolabelled with Auger-emitting 125I and encapsulated in liposomes (DSPC:Chol:DSPE-PEG) using pH-gradient loading. Single-chain fragment F5 was anchored to the liposomes as targeting device for HER2. Uptake and specificity of 125I-Comp1 delivered via targeting and non-targeting liposomes were analysed in cultured HER2-overexpressing SKOV3 and SKBR3 cells. Cell-killing efficacy was evaluated in SKOV3 cells and biodistribution for up to 48 hours was studied after intra-peritoneal injection in tumour-bearing female Balb/c nu/nu mice.

Results: 125I-Comp1 was specifically taken up by the cultured cells when administered by means of HER2-targeted liposomes and a clear dose-effect correlation in survival of cells was seen with increasing specific activity. The biodistribution studies revealed that 125I-Comp1 accumulated in tumours when distributed using HER2-targeted liposomes and that this effect was absent when using non-targeting liposomes.

Conclusion: The HER2-targeted liposomes possess the properties needed to bring about tumour-specific delivery and therapeutic effect of 125I-Comp1.

 

Place, publisher, year, edition, pages
2011. Vol. 19, no 9, 846-855 p.
National Category
Chemical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-147028DOI: 10.3109/1061186X.2011.589436ISI: 000295889800013OAI: oai:DiVA.org:uu-147028DiVA: diva2:399741
Available from: 2011-02-23 Created: 2011-02-23 Last updated: 2017-12-11Bibliographically approved
In thesis
1. Two-Step Targeting for Effective Radionuclide Therapy: Preclinical Evaluation of 125I-labelled Anthracycline Delivered by Tumour Targeting Liposomes
Open this publication in new window or tab >>Two-Step Targeting for Effective Radionuclide Therapy: Preclinical Evaluation of 125I-labelled Anthracycline Delivered by Tumour Targeting Liposomes
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

For the treatment of cancer, Auger-electron emitting radionuclides are strongly dependent on their close proximity to DNA to utilize the local therapeutic potential of the Auger electrons. This thesis investigates a two-step targeting approach that uses targeting liposomes for the delivery of an Auger-electron emitter, 125I, coupled to a DNA-binding compound, Comp1, to the tumour-cell DNA. In the first step the liposome targets overexpressed cell-surface receptors. Receptors belonging to epidermal growth factor receptor (EGFR) family are overexpressed in a number of different cancers and are therefore suitable targets. The second step is transportation of the radionuclide to the cell nucleus utilizing a DNA-binding compound. The DNA-binder used in this thesis is a daunorubicin derivative called Comp1. Papers I and II are in vitro characterizations of the targeting liposomes. Both EGFR- and HER2-targeting liposomes delivered 125I-Comp1 receptor specifically to tumour cells, and were efficient in decreasing growth of cultured tumour cells. Paper II also included a biodistribution of 125I-Comp1 delivered by HER2-targeting liposomes in tumour-bearing mice. The results gave a time-dependent uptake in tumours differed from when non-targeting liposomes encapsulating 125I-Comp1 were given. Paper III investigates the therapeutic effect of 125I-Comp1 delivered by HER2-targeting liposomes, in an animal model that mimics a situation of disseminated tumour cells in the abdomen. 125I-Comp1 delivered by HER2-targeting liposomes effectively prolonged survival of the mice in a dose-dependent relation. Several mice in the groups receiving the highest doses were tumour-free at the end of the study. Paper IV compares different lipid compositions of the liposomes with respect to leakage, cellular uptake and therapeutic efficacy of delivered 125I-Comp1on cultured cells. Liposomes containing sphingomyelin or dihydrosphingomyelin retained drug more efficiently and exhibited more receptor specific delivery properties than distearoylglycerophosphatidylcholine (DSPC) containing liposomes. However, it was the DSPC-containing liposomes that displayed best growth inhibition on cultured tumour cells. The thesis concludes that 125I-Comp1 delivered by targeting liposomes is a promising candidate for effective radionuclide therapy.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2011. 100 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 708
Keyword
radionuclide, Auger electrons, liposomes, targeting, tumour therapy
National Category
Other Basic Medicine
Research subject
Biomedical Radiation Science
Identifiers
urn:nbn:se:uu:diva-159365 (URN)978-91-554-8172-8 (ISBN)
Public defence
2011-11-12, Rudbecksalen, Dag Hammarskjölds väg 20, Uppsala, 09:15 (Swedish)
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Supervisors
Available from: 2011-10-21 Created: 2011-09-29 Last updated: 2011-11-04Bibliographically approved

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Fondell, AmelieEdwards, KatarinaUnga, JohanGedda, Lars

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