Cationic albumin conjugated pegylated nanoparticle with its transcytosis ability and little toxicity against blood–brain barrier

• Published in: International journal of pharmaceutics 2005-05, Vol.295 (1), p.247-260
• Main Authors: Lu, Wei, Tan, Yu-Zhen, Hu, Kai-Li, Jiang, Xin-Guo
• Format: Article
• Language: English
• Subjects: Animals; Astrocytes - metabolism; Biological and medical sciences; Biological Transport; Blood-Brain Barrier; Blood–brain barrier (BBB); Cationic bovine serum albumin (CBSA); Cattle; Cells, Cultured; Coculture; Coculture Techniques; Drug Carriers; Endothelial Cells - metabolism; General pharmacology; Medical sciences; Nanostructures; Pegylated nanoparticle; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Polyethylene Glycols - administration & dosage; Rats; Rats, Sprague-Dawley; Serum Albumin, Bovine - administration & dosage; Tight Junctions - physiology; Toxicity; Transcytosis
• ISSN: 0378-5173; 1873-3476
• DOI: 10.1016/j.ijpharm.2005.01.043

Our newly developed drug delivery carrier, cationic bovine serum albumin (CBSA) conjugated with poly(ethyleneglycol)-poly(lactide) (PEG-PLA) nanoparticle (CBSA-NP), was designed for brain drug delivery. CBSA, as a brain specific targetor, was covalently conjugated with the maleimide function group at the distal of poly(ethyleneglycol) (PEG) surrounding the nanoparticles. To evaluate its blood–brain barrier (BBB) transcytosis and toxicity against the BBB endothelial tight junction, we have explored a method of coculture with brain capillary endothelial cells (BCECs) on the top of micro-porous membrane of cell culture insert and astrocytes on the bottom side. The permeability of 14C-labeled sucrose was determined. For the CBSA-NP transcytosis study, a lipophilic fluorescent probe, 6-coumarin, was incorporated into nanoparticles. The BBB permeability of CBSA-NP in vitro was calculated and compared with native bovine serum albumin (BSA) conjugated pegylated nanoparticles (BSA-NP). As the coculture model, the transendothelial electrical resistance reached up to 313 ± 23 Ω cm 2. The tight junction between BCECs in the coculture could be visualized by scanning electron microscopy and transmission electron microscopy. The unchanged permeability of 14C-labeled sucrose comparing to that in the appearance of 200 μg/ml of CBSA-NP proved that CBSA-NP did not impact the integrity of BBB endothelial tight junctions. CBSA-NP also showed little toxicity against BCECs. The permeability of CBSA-NP was about 7.76 times higher than that of BSA-NP, while the transcytosis was inhibited in the excess of free CBSA. It was concluded that CBSA-NP preferentially transported across BBB with little toxicity, which offered the possibility to deliver therapeutic agents to CNS.