Brain delivery and cellular internalization mechanisms for transferrin conjugated biodegradable polymersomes

Area of Science:

• Nanotechnology
• Biomedical Engineering
• Pharmacology

Background:

• Efficient drug delivery to the brain is challenging due to the blood-brain barrier.
• Targeted delivery systems are crucial for overcoming these limitations.
• Transferrin receptor-mediated endocytosis offers a potential pathway for brain drug delivery.

Purpose of the Study:

• To develop and characterize transferrin-conjugated biodegradable polymersomes (Tf-PO) for enhanced brain drug delivery.
• To investigate the cellular internalization mechanisms of Tf-PO.
• To evaluate the in vivo brain targeting efficiency of Tf-PO compared to unconjugated polymersomes (PO).

Main Methods:

• Polymersomes (PO) were prepared using a nanoprecipitation method.
• PO were conjugated with transferrin (Tf) to form Tf-PO.
• Cellular uptake mechanisms were studied in bEnd.3 cells.
• In vivo brain distribution was assessed in rats using fluorescent microscopy after intravenous injection.

Main Results:

• Tf-PO exhibited an average diameter of ~100 nm with ~35 Tf molecules per polymersome.
• Cellular uptake of Tf-PO in bEnd.3 cells occurred via clathrin-mediated, energy-dependent endocytosis, involving the Golgi apparatus and lysosomes.
• Intravenous administration of Tf-PO in rats resulted in significantly higher accumulation in the cerebral cortex and periventricular regions compared to PO.
• Tf-PO demonstrated a 2.8-fold increase in blood-brain barrier permeability surface area product (PS) and a 2.3-fold increase in the percentage of injected dose per gram of brain (%ID/g brain) compared to PO.

Conclusions:

• Transferrin conjugation enhances the brain delivery of biodegradable polymersomes.
• Tf-PO utilizes specific cellular pathways for uptake and intracellular transport.
• Tf-PO represents a promising nanocarrier for improving drug targeting to the brain.