Histidine-conjugated poly(amino acid) derivatives for the novel endosomolytic delivery carrier of doxorubicin.
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.
Yang
Seung Rim
SR
Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology, Guseong-dong, Yuseong-gu, Daejeon 305-701, Republic of Korea.
Lee
Hyun Jin
HJ
Kim
Jong-Duk
JD
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
D000588:Amines; D002021:Buffers; D004337:Drug Carriers; D010455:Peptides; C008965:alpha,beta-poly((2-hydroxyethyl)-aspartamide); D006639:Histidine; D004317:Doxorubicin; C009317:stearylamine