Cationic albumin conjugated pegylated nanoparticle with its transcytosis ability and little toxicity against blood-brain barrier.
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 ohms cm2. 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 microg/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.
Lu
Wei
W
Department of Pharmaceutics, School of Pharmacy, Fudan University, P.O. Box 130, Shanghai 200032, China.
Tan
Yu-Zhen
YZ
Hu
Kai-Li
KL
Jiang
Xin-Guo
XG
D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001692:Biological Transport; D001812:Blood-Brain Barrier; D002417:Cattle; D002478:Cells, Cultured; D018920:Coculture Techniques; D004337:Drug Carriers; D042783:Endothelial Cells / Q000378:metabolism; D049329:Nanostructures; D011092:Polyethylene Glycols / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012710:Serum Albumin, Bovine / Q000008:administration & dosage*; D019108:Tight Junctions / Q000502:physiology
D004337:Drug Carriers; D012710:Serum Albumin, Bovine; D011092:Polyethylene Glycols