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DOI: 10.1055/s-0039-1683599
MMP-responsive nanogels for delivery of radiopharmaceuticals across the blood brain barrier
Publication History
Publication Date:
27 March 2019 (online)
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.