Lysosomal Targeting of β-Cyclodextrin

Area of Science:

• Biochemistry
• Cell Biology
• Drug Delivery

Background:

• Beta-cyclodextrins (β-CDs) are approved therapeutics used in over 30 clinical settings.
• β-CDs show therapeutic potential for lysosomal storage disorders by binding and extracting accumulated hydrophobic metabolites.
• Lysosomal targeting of enzymes typically involves N-glycans with mannose-6-phosphate (M6P) residues.

Purpose of the Study:

• To investigate if conjugating M6P-terminated N-glycans to β-CD enhances its cellular uptake and lysosomal transport.
• To evaluate the therapeutic potential of M6P-glycan modified β-CD for lysosomal storage disorders.

Main Methods:

• Covalent attachment of a synthetic biantennary bis-M6P-terminated N-glycan to β-CD.
• Formation of a host-guest complex with a Cy5 fluorophore for visualization.
• Study of cellular internalization and lysosomal transport in a mammalian cell line using fluorescence microscopy.

Main Results:

• Attachment of M6P-glycans significantly increased the rate of β-CD cellular internalization.
• M6P-glycan conjugation also enhanced the rate of β-CD transport to the lysosome.
• Fluorescence microscopy confirmed improved cellular uptake and lysosomal trafficking of the modified β-CD.

Conclusions:

• M6P-glycan conjugation is a viable strategy to enhance β-CD cellular uptake and lysosomal delivery.
• This approach may improve the therapeutic efficacy of β-CD for treating diseases involving lysosomal metabolite accumulation.
• Targeted delivery via M6P-glycans represents a promising advancement in β-CD-based therapeutics.