title: Penetratin-functionalized PEG-PLA nanoparticles for brain drug delivery.
abstract: Nanoparticulate drug delivery system possesses distinct advantages for brain drug delivery. However, its amount that reach the brain is still not satisfied. Cell-penetrating peptides (CPPs), short peptides that facilitate cellular uptake of various molecular cargo, would be appropriate candidates for facilitating brain delivery of nanoparticles. However, such effect could be deprived by the rapid systemic clearance of CPPs-functionalized nanoparticles due to their positive surface charge. Penetratin (CPP with relatively low content of basic amino acids) was here functionalized to poly(ethylene glycol)-poly(lactic acid) nanoparticles (NP) to achieve desirable pharmacokinetic and biodistribution profiles for brain drug delivery. The obtained penetratin-NP showed a particle size of 100 nm and zeta potential of -4.42 mV. The surface conjugation of penetratin was confirmed by surface chemical compositions analysis via X-ray photo electron spectroscopy. In MDCK-MDR cell model, penetratin-NP presented enhanced cellular accumulation via both lipid raft-mediated endocytosis and direct translocation processes with the involvement of Golgi apparatus, lysosome and microtubules. In vivo pharmacokinetic and biodistribution studies showed that penetratin-NP exhibited a significantly enhanced brain uptake and reduced accumulation in the non-target tissues compared with low-molecular-weight protamine (CPP with high arginine content)-functionalized nanoparticles. These data strongly implicated that penetratin-NP might represent a promising brain-targeting drug delivery system. The findings also provided an important basis for the optimization of brain drug delivery systems via surface charge modulation.
authors: Key Laboratory of Smart Drug Delivery, Ministry of Education & PLA, School of Pharmacy, Fudan University, Lane 826, Zhangheng Road, Shanghai 201203, PR China.
authors: Huimin
authors: H
authors: Xia
authors: Xiaoling
authors: X
authors: Gao
authors: Guangzhi
authors: G
authors: Gu
authors: Zhongyang
authors: Z
authors: Liu
authors: Quanyin
authors: Q
authors: Hu
authors: Yifan
authors: Y
authors: Tu
authors: Qingxiang
authors: Q
authors: Song
authors: Lei
authors: L
authors: Yao
authors: Zhiqing
authors: Z
authors: Pang
authors: Xinguo
authors: X
authors: Jiang
authors: Jun
authors: J
authors: Chen
authors: Hongzhuan
authors: H
authors: Chen
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002352:Carrier Proteins / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D002470:Cell Survival / Q000187:drug effects; D057846:Cell-Penetrating Peptides / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D003374:Coumarins / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D004285:Dogs; D004337:Drug Carriers / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D005456:Fluorescent Dyes / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008819:Mice, Nude; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013844:Thiazoles / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics
chemical_list: D002352:Carrier Proteins; D057846:Cell-Penetrating Peptides; D003374:Coumarins; D004337:Drug Carriers; D005456:Fluorescent Dyes; D013844:Thiazoles; C517282:coumarin 6; C542623:monomethoxypolyethyleneglycol-polylactide block copolymer; D011092:Polyethylene Glycols; C414409:penetratin