title: Poly(L-histidine)-PEG block copolymer micelles and pH-induced destabilization.
abstract: Poly(L-histidine)-poly(ethylene glycol) diblock copolymers (polyHis-b-PEG) were prepared and used for the construction of polymeric micelles responding to local pH changes in the body. PolyHis was synthesized by ring opening polymerization of L-histidine N-carboxyanhydride, the imidazole amine group of which was protected by the dinitrophenyl group. The resulting polymer (M(n): 5,000 g/mole) was coupled to poly(ethylene glycol) (M(n): 2,000 g/mole) via an amide linkage using the dicyclohexyl carbodiimide and N-hydroxysuccinimide-mediated reaction. The block copolymer in dimethyl sulfoxide formed polymeric micelles on diafiltration against a borate buffer at pH 8. Dynamic light scattering and atomic force microscopy showed the micelles were spherical, diameter approximately 114 nm, with a unimodal distribution. The critical micelle concentration (CMC) at pH 8.0 was 2.3 mg/l. The CMC increased markedly on decreasing the pH of the diafiltration medium below 7.2. Micelles prepared at pH 8.0 were gradually destabilized below pH 7.4, as evidenced by a slight increase in light transmittance, an alteration in size distribution, and a decrease in the pyrene fluorescence intensity. It was concluded that the ionization of the polyHis block forming the micelle core determined the pH-dependent CMC and stability. After further optimization of the pH-sensitivity, pH-sensitive micelles are expected to have application for solid tumor treatment, exploiting the fact that most solid tumors have an acidic extracellular pH.
authors.affiliation: Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, 421 Wakara Way, Suite 315, Salt Lake City, UT 84108, USA.
authors.forename: Eun Seong
authors.initials: ES
authors.lastname: Lee
authors.forename: Hyun Joon
authors.initials: HJ
authors.lastname: Shin
authors.forename: Kun
authors.initials: K
authors.lastname: Na
authors.forename: You Han
authors.initials: YH
authors.lastname: Bae
mesh_terms: D002021:Buffers; D002626:Chemistry, Pharmaceutical; D004339:Drug Compounding; D004355:Drug Stability; D006863:Hydrogen-Ion Concentration; D007202:Indicators and Reagents / Q000138:chemical synthesis / Q000737:chemistry; D008823:Micelles; D008970:Molecular Weight; D010316:Particle Size; D011092:Polyethylene Glycols / Q000138:chemical synthesis / Q000737:chemistry*; D011506:Proteins / Q000138:chemical synthesis / Q000737:chemistry*; D013050:Spectrometry, Fluorescence; D013997:Time Factors
chemical_list: D002021:Buffers; D007202:Indicators and Reagents; D008823:Micelles; D011506:Proteins; C480317:polyhistidine-block-polyethylene glycol; D011092:Polyethylene Glycols