Nuklearmedizin 2019; 58(02): 148
DOI: 10.1055/s-0039-1683599
Poster
Radiochemie und -pharmazie
Georg Thieme Verlag KG Stuttgart · New York

MMP-responsive nanogels for delivery of radiopharmaceuticals across the blood brain barrier

A Morgenroth
1   Universitätsklinikum der RWTH Aachen, Klinik für Nuklearmedizin, Aachen
,
N Drude
1   Universitätsklinikum der RWTH Aachen, Klinik für Nuklearmedizin, Aachen
,
S Singh
2   RWTH Aachen University, DWI -Leibniz-Institute for Interactive Materials, Aachen
,
L Henkel
3   RWTH Aachen University, Institute of Organic Chemistry, Aachen
,
AT Vogg
1   Universitätsklinikum der RWTH Aachen, Klinik für Nuklearmedizin, Aachen
,
M Möller
2   RWTH Aachen University, DWI -Leibniz-Institute for Interactive Materials, Aachen
,
FM Mottaghy
1   Universitätsklinikum der RWTH Aachen, Klinik für Nuklearmedizin, Aachen
› Author Affiliations
Further Information

Publication History

Publication Date:
27 March 2019 (online)

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    Ziel/Aim:

    Therapeutic interventions in brain tumors are mainly hampered by the blood-brain barrier (BBB) which prevents most drugs from entering the brain at therapeutic concentrations. Herein we synthesized a stimuli sensitive nanogel (NG) for efficient delivery of 5-I-125-Iodo-4'-thio-2'-deoxyuridine (I-125-ITdU) across the BBB.

    Methodik/Methods:

    Nanogels were synthesized as follows: six arm star poly(ethylene oxide-co-propylene oxide) pre-polymers were cross-linked via a substrate specific for matrix metalloproteinase (MMP2/9, NG degradation at tumor site), conjugated via MMP2/9 sensitive linker with 125I-ITdU (drug release at tumor site), and functionalized with diphtheria toxin receptor (DTR) substrate CRM-197 (tumor site selective transcytosis by BBB). An in vitro model of the BBB (co-culture of endothelial cells, pericytes and astrocytes or glioblastoma cells) was used to evaluate DTR-mediated transcytosis of NG. MMP activity was evaluated by zymography. NG degradation and release of I-125-ITdU were visualized by SDS and phosphorimager. Cellular uptake and DNA-incorporation rate of I-125-ITdU were assessed by gamma counter.

    Ergebnisse/Results:

    Functionalization with CRM-197 enhanced transcytosis of NG across BBB and its uptake by glioblastoma U87 cells. Increased MMP2/9 activity mediated an efficient degradation of NG and release of I-125-ITdU at tumor site. After 4h, released I-125-ITdU was efficiently internalized by the tumor cells followed by a high DNA-incorporation rate (12 ± 2% of cellular I-125-ITdU).

    Schlussfolgerungen/Conclusions:

    We present an innovative concept of enzymatic degradable I-125-ITdU-CRM-197-nanogels for delivery of nano-irradiation across the challenging BBB with the aim to improve therapy of glioblastoma.


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