Enhanced BBB and BBTB penetration and improved anti-glioma behavior of Bortezomib through dual-targeting nanostructured lipid carriers

Mar 18, 2022Journal of controlled release : official journal of the Controlled Release Society

Improved Brain Barrier Penetration and Anti-Glioma Effects of Bortezomib Using Dual-Targeting Lipid Nanocarriers

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Abstract

Dual nanostructured lipid carriers (NLCs) modified with D8 and RI-VAP demonstrated superior targeting capabilities for glioma treatment.

D8 targets nicotine acetylcholine receptors on brain capillary endothelial cells, facilitating efficient penetration through the blood-brain barrier.
RI-VAP is a ligand for a specific cancer marker on the surface of glioma cells, allowing for enhanced delivery across the blood-brain tumor barrier.
Dual NLCs showed high specificity in internalizing into brain endothelial cells, tumor neovascular cells, and glioma cells.
In vitro models indicated that Dual NLCs penetrated the blood-brain barrier and blood-brain tumor barrier more effectively than non-targeted or mono-targeted NLCs.
When loaded with Bortezomib, Dual NLCs exhibited the highest therapeutic efficiency, leading to improved cytotoxicity, apoptosis, and prolonged survival in mice with gliomas.

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The effective treatment of glioma through conventional chemotherapy is proved to be a great challenge in clinics. The main reason is due to the existence of two physiological and pathological barriers respectively including the blood-brain barrier (BBB) and blood-brain tumor barrier (BBTB) that prevent most of the chemotherapeutics from efficient delivery to the brain tumors. To address this challenge, an ideal drug delivery system would efficiently traverse the BBB and BBTB and deliver the therapeutics into the glioma cells with high selectivity. Herein, a targeted delivery system was developed based on nanostructured lipid carriers (NLCs) modified with two proteolytically stable D-peptides, D8 and RI-VAP (Dual NLCs). D8 possesses high affinity towards nicotine acetylcholine receptors (nAChRs), overexpressed on brain capillary endothelial cells (BCECs), and can penetrate through the BBB with high efficiency. RI-VAP is a specific ligand of cell surface GRP78 (csGRP78), a specific angiogenesis and cancer cell-surface marker, capable of circumventing the BBTB with superior glioma-homing property. Dual NLCs could internalize into BCECs, tumor neovascular endothelial cells, and glioma cells with high specificity and could penetrate through in vitro BBB and BBTB models with excellent efficiency compared to non-targeted or mono-targeted NLCs. In vivo whole-animal imaging and ex vivo imaging further confirmed the superior targeting capability of Dual NLCs towards intracranial glioma. When loaded with Bortezomib (BTZ), Dual NLCs attained the highest therapeutic efficiency by means of superior in vitro cytotoxicity and apoptosis and prolonged survival rate and efficient anti-glioma behavior in intracranial glioma bearing mice. Collectively, the designed targeting platform in this study could overcome multiple barriers and effectively deliver BTZ to glioma cells, which represent its potential for advanced brain cancer treatment with promising therapeutic outcomes.

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Enhanced BBB and BBTB penetration and improved anti-glioma behavior of Bortezomib through dual-targeting nanostructured lipid carriers

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