Study On The Stability And Guest Exchange Behavior Of Reduction-responsive Micelles Formed By Block Copolymer

Reduction-responsive micelles hold enormous promise for the application as drug carriers due to the fast drug release triggered by reducing conditions and high anticancer activity.However,the effect of hydrophobic chain length on the stability and guest exchange of reduction-responsive micelles,especially for the micelles formed from diblock copolymers containing single disulfide group,are not fully understood.In this thesis,we have investigated the effect of hydrophobic block on the stability and guest exchange of reduction-responsive micelles formed by disulfide-linked amphiphilic block copolymer.The main research process is as following:(1)Combining the ring opening polymerization and click chemistry,the disulfide-linked amphiphilic block copolymer with the same hydrophilic block poly(ethylene glycol)(PEG)but different chain length of the hydrophobic blockpoly(s-caprolactone)(PCL)was synthesized.The PEG-SS-PCL copolymerwas characterized by 1H NMR and GPC.A pair of FRET dyes DiO and DiI was used.PEG-SS-PCL micelles loaded with one or two kinds of dyes were prepared by the precipitation and membranedialysis method.The CMC values,sizes and distribution,weight-average molar masses,surface density of PEG were characterized.The longer PCL chain lead to lower CMC and surface density of PEG but the<Rh>and Mw of micelles increase withthe length of PCL block.The influence of the chain length of hydrophobic PCL block on the stability and guest exchange of PEG-SS-PCL micelles in the aqueous solutions containing 10 mM dithiothreitol(DTT)was studied by the use of both dynamic laser light scattering(DLS)and fluorescence emission spectrum.The micelles aggregated due to the cleavage of the disulfide bondsand the shorter PCL chains lead tofaster aggregation rate.Theguest exchange of the micelles was accelerated inthe aqueous solutions containing 10 mM DTT.The guest exchange rate decreased with the increase of the PCL length,which implies thatmicelles with shorter PCL block have faster release rates.(2)Thereduction-responsive FRET micelles were also used to study the interaction between micelles and Hela cells.The internalization of PEG-SS-PCL micelles in vitro measured by flow cytometric analysis and FRET imaging shows that micelles with longer hydrophobic chains exhibit higher cellular internalization,which indicatesthat higher cell uptake of micelles with longer PCL block compensates the slower guest release.FRET imaging taken by confocal fluorescence microscope shows that the release of dyes loaded in reduction-responsive micelles is much faster than normal micelles.A part of PEG-SS-PCL micelles release the guest molecules on the cell membrane.Some micelles internalize into the cellsby whole and then start to release the dyes.The dyes released from the micelles distribute on cellmembrane and in cellinterior.