Triple Stimuli-Responsive and Doxorubicin-Conjugated Polymeric Mixed Micelles with Acid-Labile Linkage and Forster Resonance Energy Transfer for Controlled Drug Release

  • 陳 毅哲

Student thesis: Doctoral Thesis


The purpose of this study was to develop a drug delivery system with promising functionalities of active targeting stimuli-responsive AIE-based fluorescent tracking for potential application in controlled drug release Towards this goal we developed a drug-conjugated polymeric mixed micelle system self-assembled from two series of amphiphilic block copolymers PCL-b-P(TEGMA-co-PPSEMA) with aggregation-induced emission (AIE) characteristic and doxorubicin-conjugated DOX-hyd-PCL-SS-b-P(TEGMA-co-FA) with active targeting and triple stimuli-responsive features In this research we investigated the nanostructure morphology stimuli-responsive fluorescent properties drug release and cytotoxicity to HeLa cells of the multifunctional drug-conjugated mixed micelle Poly(?-caprolactone) (PCL) is the hydrophobic core of polymeric micelle The hydrophobic anticancer drug doxorubicin (DOX) was connected to the chain end of poly(ε-caprolactone) (PCL) backbone via pH-responsive hydrazone linkers The thermo-responsive monomer triethylene glycol methacrylate (TEGMA) is the hydrophilic shell of micelle that makes the micelle water-soluble and be able to self-assemble in aqueous solution Futhermore the disulfide bond between hydrophobic and hydrophilic blocks is redox responsive We also introduced pH-responsive and active targeting ligands folic acid (FA) to hydrophilic block of DOX-hyd-PCL-SS-b-P(TEGMA-co-FA) and the fluorescent moieties 2-(1 2 3 4 5-pentaphenyl-1H-silol-yloxy) ethyl methacrylate) (PPSEMA) were connected to the other copolymer PCL-b-P(TEGMA-co-PPSEMA) Since HeLa cells are overexpressing folate receptor (FR) folic acid (FA) is often employed to functionalize the hydrophilic shell of micelles for an active tumor targeting and thus to effectively promote cell-specific drug uptake Due to the pH variation among cellular compartments such as endosomes and lysosomes (pH ? 5 0) extracellular tumor tissues (pH ? 6 5) and normal tissues (pH 7 4) we introduced a pH-responsive chemical linker hydrazone bond (hyd) to mixed micelle system which can be cleaved in acidic environment Also we adjusted the degree of polymerization of TEGMA and FA and changed the ratio of DOX-hyd-PCL-SS-b-P(TEGMA-co-FA) and PCL-b-P(TEGMA-co-PPSEMA) in mixed micelles to control the lower critical solution temperature (LCST) The LCST should be higher than body temperature (37 °C) in neutral environment but lower than 37 °C when in acidic environment so the micelles can be steady in blood circulation and release drug in lysosome of tumor cells Because of the much higher concentration of glutathione (GSH) (approximately 10 mM) in tumor cytosol than the normal cells the disulfide bonds (SS) could be cleaved under such high reductive environment F?rster Resonance Energy Transfer (FRET) would occur when donor was close enough to acceptor owing to the spectral overlap of PPSEMA and DOX The FRET phenomenon could serve as a basis for monitoring the drug conjugation or release from the micelles In addition in vitro results demonstrated that the drug-conjugated mixed micelles exhibited dose-dependent cytotoxicity to HeLa cells
Date of Award2020
Original languageEnglish
SupervisorWen-Chung Wu (Supervisor)

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