Poly( l-histidine)–PEG block copolymer micelles and pH-induced destabilization

• Published in: Journal of controlled release Vol. 90; no. 3; pp. 363 - 374
• Main Authors: Lee, Eun Seong, Shin, Hyun Joon, Na, Kun, Bae, You Han
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 31.07.2003; Elsevier
• Subjects: Biological and medical sciences; Block copolymer; Buffers; Chemistry, Pharmaceutical; Drug Compounding; Drug Stability; Extracellular tumor pH; General pharmacology; Hydrogen-Ion Concentration; Indicators and Reagents - chemical synthesis; Indicators and Reagents - chemistry; Medical sciences; Micelles; Molecular Weight; Particle Size; PEG; pH-sensitive micelle; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Poly( l-histidine); Polyethylene Glycols - chemical synthesis; Polyethylene Glycols - chemistry; Proteins - chemical synthesis; Proteins - chemistry; Spectrometry, Fluorescence; Time Factors; Poly( l-histidine); pH-sensitive micelle; PEG; Block copolymer; Extracellular tumor pH; Particle size; Stability; Pharmaceutical technology; Control release polymer; Poly(L-histidine); Micelle; Drug carrier; Lysine polymer; Histidine polymer; Ethylene oxide polymer; Micellar critical concentration; Dosage form; pH
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/S0168-3659(03)00205-0

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 ∼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.