Reduction-Sensitive Reversibly Crosslinked Biodegradable Micelles For Triggered Release Of Doxorubicin

In this thesis, the reduction-sensitive reversibly interfacial crosslinked micelle was prepared. By introducing crosslinkably groups, lipoic acid, in between the biodegradable biocompatible PEG-PCL, the micelles can be reversibly crosslinked in the interface of the micelles as catalyzed by DTT. Thus crosslinked micelles demonstrated markedly enhanced stability, while they dissociated in mimicking intracellular reductive environment.(1) In the first part, the block polymer of poly(ethylene glycol) (PEG) and poly(ε-caprolactone) (PCL) containing two lipoyl functional groups at their interface (PEG-L2-PCL) was synthesized. 1H NMR and gel permeation chromatography (GPC) measurements shows that PEG-L2-PCL block copolymer had a controlled composition and a polydispersity index (PDI) of 1.36. PEG-L2-PCL formed micelles with sizes ranging from 20 to 150 nm in aqueous solutions, wherein a critical micelle concentration (CMC) of 16 mg/L was determined. The micelles were readily crosslinked by adding 7.6 mol.% dithiothreitol (DTT) relative to lipoyl groups. Notably, micelles after crosslinking demonstrated markedly enhanced stability against dilution, physiological salt concentration and organic solvent. In the presence of 10 mM DTT, however, micelles were subject to rapid de-crosslinking. In vitro release studies showed minimal release of DOX from crosslinked micelles at a concentration of 10 mg/L (C < CMC), wherein less than 15 % DOX was released in 10 h. In contrast, rapid release of DOX was observed for DOX-loaded non-crosslinked micelles under otherwise the same conditions (ca. 80 % release in 0.5 h). In the presence of 10 mM DTT mimicking intracellular reductive environment, sustained release of DOX from crosslinked micelles was achieved, in which 75 % DOX was released in 9 h. (2) In the second part, the block polymer of poly(ethylene glycol)-poly(2-Hydroxyethyl methacrylate)-poly(2-Hydroxyethyl methacrylate- g - polylactide) (PEG-PHEMA-P(HEMA-g-PLA)11 containing two lipoyl functional groups on the side chain (PEG-PHEMA-Lx-P(HEMA-g-PLA)11) was synthesized. 1H NMR and GPC measurements showed that PEG-PHEMA-P(HEMA-g-PLA) block copolymer had a controlled composition and a polydispersity index (PDI) of 1.12. PEG-PHEMA-Lx-P(HEMA-g-PLA)11 formed micelles with sizes ranging from 50 to 150 nm in aqueous solutions. The micelles were readily crosslinked by adding 10 mol.% dithiothreitol (DTT) relative to lipoyl groups. Notably, micelles after crosslinking demonstrated markedly enhanced stability against dilution and organic solvent. In the presence of 10 mM DTT mimicking intracellular reductive environment, the micelles de- crosslinked in 3h.