Intracellular delivery mechanism and brain delivery kinetics of biodegradable cationic bovine serum albumin-conjugated polymersomes

Abstract

Background: A novel brain drug delivery system using cationic bovine serum albumin (CBSA)-conjugated biodegradable polymersomes (CBSA-PO) was prepared, and its intracellular delivery mechanism and brain delivery kinetics were evaluated. Methods and results: Biodegradable poly(ethylene glycol)-poly(ε-caprolactone) (PEG-PCL) was used to prepare the polymersomes, and thiolated CBSA was conjugated with the surface of the polymersome. Transmission electron microscopy and dynamic light scattering showed that the CBSA-PO had a round and vesicle-like shape, with a mean diameter of around 100 nm. Coupling of CBSA with polymersomes was confirmed by X-ray photoelectron spectroscopy. Uptake of CBSA-PO by bEnd.3 cells was significantly higher than that of unconjugated polymersomes, but was inhibited by low temperature, free CBSA, and poly-L-lysine, indicating that endocytosis was energy-driven and absorptive-mediated. Cell viability assays confirmed the good safety profile of biodegradable CBSA-PO. Pharmacokinetic results demonstrated that the polymersomes had long circulation times, and CBSA conjugation on the polymersomes significantly increased the blood-brain barrier permeability surface area product by 3.6-fold and the percentage of injected dose per gram brain (% ID/g brain) by 2.1-fold. Capillary depletion experiments showed that CBSA-PO was distributed into the brain parenchyma in a time-dependent manner, with few polymersomes detected, indicating that conjugation of polymersomes with CBSA significantly improved their transcytosis across the brain-blood barrier. Conclusion: These results suggest that CBSA-PO is a promising drug brain delivery carrier with low toxicity.

Drug-Loaded Nanoparticle Systems And Adult Stem Cells: A Potential Marriage For The Treatment Of Malignant Glioma?

“…Beyond particle size, nanoparticles have been modified with cationic bovine serum albumin (CBSA), aclarubicin-loaded CBSA, or polysobate 80 surfactant, and these modifications have resulted in more robust levels of nanoparticle accumulation within the brain [ 7 , 47 , 48 ]. Also, modifying nanoparticles with lipophilic additives reduces their surface charge therefore binding apolipoprotein E (ApoE), which can enhance BBB uptake [ 49 , 50 ].…”

Adverse Effects of Non-Metallic Nanoparticles in the Central Nervous System

“…MWNTs coated with angiopep-2 were more intensively taken up by glioma-bearing brains than NPs without the ligand [72]. Enhanced accumulation in brain tissue was also observed for transferrin-loaded solid lipid NPs [73], liposomes with bovine serum albumin [74], biodegradable polymersomes with cationic bovine serum albumin [75] and antibody-coated polymer-based NPs [76]. This effect was attributed to enhanced phagocytosis by macrophages [76].…”

“…Only little toxicity (viability above 85%). [75] ICG-indocyanine green (dye), PLGA, PLG-poly(lactic-co-glicolic acid), PCL-poly(caprolatone), PLLA-poly(l-lactic acid), PEG/PLA-poly(ethylene glycol)/poly(lactide) copolymer, PAMAM-polyamidoamine, PEG-PEI-poly(ethylene glycol)/poly(ethylenimine), TEB-poly[Triphenylamine-4-vinyl-(P-methoxy-benzene)], CMCht-carboxymethylchitosan, MWNTs-multi-walled carbon nanotubes, SWCNTs-single-walled carbon nanotubes.…”

“…In addition, carbon NPs [19,21,22,32,44,97], modified PAMAM dendrimers [28,89,106], PEG-based dendrimers [107], polymer NPs [102], PEG/polyethylenimine ("nanogel") NPs modified with oligonucleotides [43], PLGA NPs modified with PEG and phage-displayed peptides [101], solid lipid NPs, as well as albumin and chitosan NPs [67,75,91,108] were also reported to be non-toxic to glial cells, neurons and endothelial cells.…”