Poly(L-histidine)-PEG block copolymer micelles and pH-induced destabilization.
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.
Lee
Eun Seong
ES
Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, 421 Wakara Way, Suite 315, Salt Lake City, UT 84108, USA.
Shin
Hyun Joon
HJ
Na
Kun
K
Bae
You Han
YH
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
D002021:Buffers; D007202:Indicators and Reagents; D008823:Micelles; D011506:Proteins; C480317:polyhistidine-block-polyethylene glycol; D011092:Polyethylene Glycols