Brain delivery property and accelerated blood clearance of cationic albumin conjugated pegylated nanoparticle.
Cationic bovine serum albumin (CBSA) conjugated poly(ethyleneglycol)-poly(lactide) (PEG-PLA) nanoparticle (CBSA-NP), was designed as a novel drug carrier for brain delivery. In this paper, three formulations of CBSA-NP with different surface CBSA density as well as native bovine serum albumin conjugated nanoparticle (BSA-NP) and CBSA unconjugated pegylated nanoparticle (NP), were formulated. Their brain transcytosis across the blood-brain barrier (BBB) coculture and brain delivery in mice were investigated using 6-coumarin as fluorescent probe. By using free CBSA as specific inhibitor, it was evidenced that CBSA-NP crossed the brain capillary endothelium through absorptive mediated transcytosis. The result of transcytosis across the BBB coculture and brain delivery in mice proved that the increase of surface CBSA density of the nanoparticle enhanced the BBB permeability-surface area but decreased blood AUC. The optimized CBSA number conjugated per averaged nanoparticle was 110, with the maleimide-PEG-PLA/methoxy-PEG-PLA weight ratio 1:10, which can acquire the greatest percentage of injected dose per gram brain (%ID/g brain) by 2.3-fold compared with NP. Besides, "accelerated blood clearance phenomenon" was found through evaluating blood clearance profile of CBSA-NP post-injection of single dose or over a period of successive high doses of CBSA-NP. Understanding these issues is important for the future development of CBSA-NP as a brain delivery carrier and for the attenuation of toxicity or immunological responses to the nanodevice following a consequence of nanomedication.
Lu
Wei
W
Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai, 200032, People's Republic of China.
Wan
Jin
J
She
Zhenjue
Z
Jiang
Xinguo
X
D000818:Animals; D019540:Area Under Curve; D001692:Biological Transport; D001812:Blood-Brain Barrier; D001921:Brain / Q000098:blood supply / Q000378:metabolism*; D002196:Capillaries / Q000166:cytology / Q000378:metabolism; D002412:Cations / Q000737:chemistry; D002417:Cattle; D018920:Coculture Techniques; D003374:Coumarins / Q000737:chemistry; D004337:Drug Carriers; D042783:Endothelial Cells / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology; D005456:Fluorescent Dyes / Q000737:chemistry; D007150:Immunohistochemistry; D008297:Male; D008301:Maleimides / Q000737:chemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D008970:Molecular Weight; D053758:Nanoparticles / Q000737:chemistry*; D010316:Particle Size; D011091:Polyesters / Q000737:chemistry / Q000493:pharmacokinetics*; D011092:Polyethylene Glycols / Q000737:chemistry / Q000493:pharmacokinetics*; D011108:Polymers / Q000138:chemical synthesis / Q000737:chemistry; D012710:Serum Albumin, Bovine / Q000737:chemistry / Q000493:pharmacokinetics*
D002412:Cations; D003374:Coumarins; D004337:Drug Carriers; D005456:Fluorescent Dyes; D008301:Maleimides; D011091:Polyesters; D011108:Polymers; C499774:polyethylene glycol-polylactide-polyethylene glycol; D012710:Serum Albumin, Bovine; D011092:Polyethylene Glycols; C030123:coumarin