title: Histidine-conjugated poly(amino acid) derivatives for the novel endosomolytic delivery carrier of doxorubicin.
abstract: Direct conjugation of histidine to poly(2-hydroxyethyl aspartamide) (PHEA-His) and C18-grafted PHEA (PHEA-g-C18-His) was achieved via an ester linkage using N(alpha)-Boc-L-histidine, followed by the deprotection of Boc groups. PHEA-His series would be expected as an endosomolytic synthetic polymer because of the buffering capacity at physiological and endosomal pH regulated by alpha-amine and imidazole groups in side chains. PHEA-g-C18-His series formed stable self-aggregates due to the hydrophobic interaction between grafted alkyl chains. The size, zeta potential, and micropolarity of PHEA-g-C18-His series greatly increased at pH 5.0, because aggregates swelled by a positive surface charge and the electrostatic repulsion of ionized histidine moieties in the aggregate surface. In the confocal microscopy, it was revealed that PHEA-g-C18-His was more uniformly distributed than PHEA-g-C18 in HeLa cells after 8 h of incubation and was attributed to the endosomolytic ability of conjugated histidine moieties. In doxorubicin-loaded self-aggregate systems, the histidine conjugation improved the cell cytotoxicity by a fast release of loaded doxorubicin at low pH and the endosomolytic ability of conjugated histidine, resulting in the easy nuclear access of doxorubicin.
authors.affiliation: Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology, Guseong-dong, Yuseong-gu, Daejeon 305-701, Republic of Korea.
authors.forename: Seung Rim
authors.initials: SR
authors.lastname: Yang
authors.forename: Hyun Jin
authors.initials: HJ
authors.lastname: Lee
authors.forename: Jong-Duk
authors.initials: JD
authors.lastname: Kim
mesh_terms: D000588:Amines / Q000737:chemistry; D002021:Buffers; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D004337:Drug Carriers / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D004705:Endocytosis; D011992:Endosomes / Q000378:metabolism*; D006367:HeLa Cells; D006639:Histidine / Q000737:chemistry*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D009682:Magnetic Resonance Spectroscopy; D018613:Microscopy, Confocal; D015394:Molecular Structure; D010316:Particle Size; D010455:Peptides / Q000737:chemistry*; D013057:Spectrum Analysis; D055672:Static Electricity; D013499:Surface Properties
chemical_list: D000588:Amines; D002021:Buffers; D004337:Drug Carriers; D010455:Peptides; C008965:alpha,beta-poly((2-hydroxyethyl)-aspartamide); D006639:Histidine; D004317:Doxorubicin; C009317:stearylamine