Folic Acid-Conjugated Brush Polymers Show Enhanced Blood–Brain Barrier Crossing in Static and Dynamic In Vitro Models Toward Brain Cancer Targeting Therapy

Title data

Mazrad, Zihnil A. I. ; Refaat, Ahmed ; Morrow, Joshua P. ; Voelcker, Nicolas H. ; Nicolazzo, Joseph A. ; Leiske, Meike N. ; Kempe, Kristian:
Folic Acid-Conjugated Brush Polymers Show Enhanced Blood–Brain Barrier Crossing in Static and Dynamic In Vitro Models Toward Brain Cancer Targeting Therapy.
In: ACS Biomaterials Science & Engineering. Vol. 10 (2024) Issue 5 . - pp. 2894-2910.
ISSN 2373-9878
DOI: https://doi.org/10.1021/acsbiomaterials.3c01650

Official URL:

Abstract in another language

Over the past decades, evidence has consistently shown that treatment of central nervous system (CNS)-related disorders, including Alzheimer’s disease, Parkinson’s disease, stroke, multiple sclerosis, and brain cancer, is limited due to the presence of the blood–brain barrier (BBB). To assist with the development of new therapeutics, it is crucial to engineer a drug delivery system that can cross the BBB efficiently and reach target cells within the brain. In this study, we present a potentially efficient strategy for targeted brain delivery through utilization of folic acid (FA)-conjugated brush polymers, that specifically target the reduced folate carrier (RFC, SLC19A1) expressed on brain endothelial cells. Here, azide (N3)-decorated brush polymers were prepared in a straightforward manner coupling a heterotelechelic α-NH2, ω-N3-poly(2-ethyl-2-oxazoline) (NH2-PEtOx-N3) to N-acylated poly(amino ester) (NPAE)-based brushes. Strain-promoted azide–alkyne cycloaddition (SPAAC) ‘click chemistry’ with DBCO-folic acid (FA) yielded FA-brush polymers. Interestingly, while azide functionalization of the brush polymers dramatically reduced their association to brain microvascular endothelial cells (hCMEC/D3), the introduction of FA to azide led to a substantial accumulation of the brush polymers in hCMEC/D3 cells. The ability of the polymeric brush polymers to traverse the BBB was quantitatively assessed using different in vitro BBB models including static Transwell and microfluidic platforms. FA-brush polymers showed efficient transport across hCMEC/D3 cells in a manner dependent on FA composition, whereas nonfunctionalized brush polymers exhibited limited trafficking under the same conditions. Further, cellular uptake inhibition studies suggested that the interaction and transport pathway of FA-brush polymers across BBB relies on the RFC-mediated pathways. The potential application of the developed FA-brush polymers in brain cancer delivery was also investigated in a microfluidic model of BBB-glioblastoma. Brush polymers with more FA units successfully presented an enhanced accumulation into U-87 MG glioma cells following its BBB crossing, compared to controls. These results demonstrate that FA-modified brush polymers hold a great potential for more efficient delivery of future brain therapeutics.

Further data

Item Type:	Article in a journal
Refereed:	Yes
Additional notes:	PMID: 38556768
Institutions of the University:	Faculties > Faculty of Biology, Chemistry and Earth Sciences > Department of Chemistry Faculties > Faculty of Biology, Chemistry and Earth Sciences > Department of Chemistry > Junior Professor Sustainable and Functional Polymer Systems > Junior Professor Sustainable and Functional Polymer Systems - Juniorprof. Dr. Meike Leiske
Result of work at the UBT:	Yes
DDC Subjects:	500 Science > 540 Chemistry
Date Deposited:	31 Jan 2025 07:46
Last Modified:	31 Jan 2025 07:46
URI:	https://eref.uni-bayreuth.de/id/eprint/92257