title: N-acetyl histidine-conjugated glycol chitosan self-assembled nanoparticles for intracytoplasmic delivery of drugs: endocytosis, exocytosis and drug release.
abstract: Nano-sized vesicular systems (nanoparticles), ranging from 10 nm to 1000 nm in size, have potential applications as drug delivery systems. Successful clinical applications require the efficient intracellular delivery of drug-loaded nanoparticles. Here we describe N-acetyl histidine-conjugated glycol chitosan (NAcHis-GC) self-assembled nanoparticles as a promising system for intracytoplasmic delivery of drugs. Because N-acetyl histidine (NAcHis) is hydrophobic at neutral pH, the conjugates formed self-assembled nanoparticles with mean diameters of 150-250 nm. In slightly acidic environments, such as those in endosomes, the nanoparticles were disassembled due to breakdown of the hydrophilic/hydrophobic balance by the protonation of the imidazole group of NAcHis. Cellular internalization and drug release of the pH-sensitive self-assembled nanoparticles were investigated by flow cytometry and confocal microscopy. NAcHis-GC nanoparticles internalized by adsorptive endocytosis were exocytosed or localized in endosomes. The amount of exocytosed nanoparticles was dependent on the pre-incubation time prior to removal of free nanoparticles from the culture media. Flow cytometry and confocal microscopy showed that NAcHis-GC nanoparticles released drugs into the cytosol and cell cycle analysis demonstrated that paclitaxel-incorporated NAcHis-GC nanoparticles were effective in inducing arrest of cell growth.
authors.affiliation: Asan Institute for Life Sciences, University of Ulsan College of Medicine, 388-1 Pungnap-2dong, Songpa-gu, Seoul 138-736, Korea.
authors.forename: Ji Sun
authors.initials: JS
authors.lastname: Park
authors.forename: Tae Hee
authors.initials: TH
authors.lastname: Han
authors.forename: Kuen Yong
authors.initials: KY
authors.lastname: Lee
authors.forename: Sung Soo
authors.initials: SS
authors.lastname: Han
authors.forename: Jung Jin
authors.initials: JJ
authors.lastname: Hwang
authors.forename: Dae Hyuk
authors.initials: DH
authors.lastname: Moon
authors.forename: Sang Yoon
authors.initials: SY
authors.lastname: Kim
authors.forename: Yong Woo
authors.initials: YW
authors.lastname: Cho
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000737:chemistry; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D048271:Chitosan / Q000737:chemistry*; D016503:Drug Delivery Systems; D004705:Endocytosis / Q000187:drug effects*; D005089:Exocytosis / Q000187:drug effects*; D005434:Flow Cytometry; D016650:Fluorescein-5-isothiocyanate; D005456:Fluorescent Dyes; D006639:Histidine / Q000031:analogs & derivatives* / Q000737:chemistry; D006801:Humans; D018613:Microscopy, Confocal; D049329:Nanostructures; D017239:Paclitaxel / Q000008:administration & dosage / Q000737:chemistry; D010316:Particle Size
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D005456:Fluorescent Dyes; D006639:Histidine; D048271:Chitosan; D016650:Fluorescein-5-isothiocyanate; C023495:N-acetylhistidine; D017239:Paclitaxel