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

Abstract

Zhiqing Pang,1,2 Huile Gao,1,2 Jun Chen,1,2 Shun Shen,1,2 Bo Zhang,3 Jinfeng Ren,1,2 Liangran Guo,1,2 Yong Qian,1,2 Xinguo Jiang,1,2 Heng Mei31Department of Pharmaceutics, School of Pharmacy, 2Key Laboratory of Smart Drug Delivery, Ministry of Education and PLA, Fudan University, Shanghai, 3Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of ChinaBackground: 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.Keywords: brain delivery kinetics, biodegradable polymersomes, cationic albumin, brain–blood barrier