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pH Dependent Drug Release System Using Micelles Stabilized by Cationic Drugs
차의준,김주은,안철희 한국고분자학회 2010 Macromolecular Research Vol.18 No.7
Doxorubicin, which is a positively charged anti-cancer drug, was encapsulated into the micelles formed by copolymers consisting of methoxy poly(ethylene glycol), negatively charged aspartic acid oligomer and poly(ε-caprolactone) (mPEG-Asp-PCL). The micelles showed an intensity-averaged diameter of 73.0 ± 30.6 nm measured by dynamic light scattering. The diameter of doxorubicin loaded micelles increased slightly to 75.8 ± 26.2 nm. The doxorubicin-loading and efficiency into the micelles were 15.1% and 44.5%, respectively. The drug-loaded micelles were stabilized ionically using divalent calcium cations and displayed a size of 78.1 ± 24.3 nm. The stabilized micelles showed the typical two-phase release patterns, which were the relatively rapid release of 53% doxorubicin in the first 24 h, and then showed the sustained release to 65% of more than 90 h. On the other hand, doxorubicin release from the non-stabilized micelles was retarded and did not exceed 5% in 24 h because the positively charged doxorubicin at pH 7.4 in the absence of cations was still retained in the micelles through ionic interactions with the carboxylic acids of aspartic acid residues. At pH 3.0, the carboxylic acids became protonated and the neutralization of the charges led to an absence or decrease in the ionic interactions, which resulted in the abrupt release of doxorubicin up to 41% from the non-stabilized micelles after a change in pH and steeper release profiles up to 59% in 90 h.
차의준,안철희,선인철,이상천,권익찬,김광명 한국고분자학회 2012 Macromolecular Research Vol.20 No.3
Methoxy-poly(ethylene glycol) (mPEG)-Asp-Cys was synthesized by ring opening polymerization, and its characterization by 1H nuclear magnetic resonance (NMR) showed that the copolymer has 18 aspartic acid units and 0.95 cysteine units on average, with the molecular weight and distribution of 13.1 k and 1.15. PEGylated AuNP with doxorubicin containing CaP layers was prepared to have the size of 79.8±18.7 nm by light scattering measurement method, with the CaP thickness around 27 nm. PEGylated Dox-AuNP@CaP was stable in the physiological conditions for several weeks in the presence of glutathione. Loading amount and efficiency of doxorubicin into the particles were 1.3% and 27.9%, respectively. The loading amount was 1.3%, lower than common organic selfassembled carriers, because of the relatively high atomic mass of gold. In vitro release experiments were performed in two different environments: extracellular fluid (pH 7.4) and intracellular lyosomal fluid (pH 4.5). The amount of released doxorubicin from PEGylated Dox-AuNP, without CaP layer, exceeds 60% in 2 h. In contrast, PEGylated Dox-AuNP@CaP effectively limited the doxorubicin release in the extracellular condition to 13% after 12 h, and changing the media to the intracellular lysosomal condition resulted in a triggered release of doxorubicin from 7%to 78% in an additional 4 h. Cell viability of PEGylated Dox-AuNP@CaP and PEGylated AuNP@CaP were estimated with HeLa cells by MTT assay. Cell viability of PEGylated Dox-AuNP@CaP came down to 19% after 24 h incubation, while the PEGylated AuNP@CaP particle itself showed slight cytotoxicity with the same conditions. The prepared PEGylated Dox-AuNP@CaP worked as a pH- and ion concentration-sensitive drug-delivery system as well as theranostic nanoparticles for CT imaging and cancer treatment.