Protease Responsive Nanogels for Transcytosis across the Blood-Brain Barrier and Intracellular Delivery of Radiopharmaceuticals to Brain Tumor Cells.

Abstract

Despite profound advances in treatment approaches, gliomas remain associated with very poor prognoses. The residual cells after incomplete resection often migrate and proliferate giving a seed for highly resistant gliomas. The efficacy of chemotherapeutic drugs is often strongly limited by their poor selectivity and the blood brain barrier (BBB). Therefore, the development of therapeutic carrier systems for efficient transport across the BBB and selective delivery to tumor cells remains one of the most complex problems facing molecular medicine and nano-biotechnology. To address this challenge, a stimuli sensitive nanogel is synthesized using pre-polymer approach for the effective delivery of nano-irradiation. The nanogels are cross-linked via matrix metalloproteinase (MMP-2,9) substrate and armed with Auger electron emitting drug 5-[125 I]Iodo-4"-thio-2"-deoxyuridine ([125 I]ITdU) which after release can be incorporated into the DNA of tumor cells. Functionalization with diphtheria toxin receptor ligand allows nanogel transcytosis across the BBB at tumor site. Functionalized nanogels efficiently and increasingly explore transcytosis via BBB co-cultured with glioblastoma cells. The subsequent nanogel degradation correlates with up-regulated MMP2/9. Released [125 I]ITdU follows the thymidine salvage pathway ending in its incorporation into the DNA of tumor cells. With this concept, a highly efficient strategy for intracellular delivery of radiopharmaceuticals across the challenging BBB is presented.

• Authors: Smriti Singh, Natascha Drude, Lena Blank, Prachi Bharat Desai, Hiltrud Königs, Stephan Rütten, Karl-Josef Langen, Martin Möller, Felix M Mottaghy, Agnieszka Morgenroth
• Journal: Advanced healthcare materials (Adv Healthc Mater) Vol. 10 Issue 20 Pg. e2100812 (10 2021) ISSN: 2192-2659 [Electronic] Germany
• PMID: 34490744 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 The Authors. Advanced Healthcare Materials published by Wiley-VCH GmbH.

Chemical References

• Nanogels
• Radiopharmaceuticals
• Peptide Hydrolases

Topics

• Blood-Brain Barrier
• Brain Neoplasms (drug therapy)
• Drug Delivery Systems
• Humans
• Nanogels
• Peptide Hydrolases
• Radiopharmaceuticals
• Transcytosis