| Nanosized micelles formed by self-assembly of amphiphilic.copolymer are one of most ideal nano-carriers for hydrophobic antitumor drugs.As these nanosized micelles injected into the body,were subject to dissocation and premature drug release because of extensive dilution and interactions with biomolecules,resulting in low tumor targeting efficiency and the treatment effect is poor.Their stability may be enhanced by cross-linking.However,how can the stably cross-linked nanosized micelles release quickly at the lesion site become a key point.On the other hand,chemical bonding can also be used to reduce premature drug release in the transport process.Based on the above background,two kinds of reduced response nanosized micelles were prepared in this paper.The drug release behavior was studied by using doxorubicin(DOX)as drug model.In this thesis,the amphiphilic polymer dextran-selenoctanoic acid derivative were synthesized by using natural macromolecular dextran as raw material and selenoicpoic acid which containing diselenide bonds in its side chain modification,then self-assembled in water and crosslinking with dithiocarbol(DTT)to form diselenide-crosslinked dextran nanosized micelles.The nanisized micelles were used to trigger the release of doxorubicin.The experimental results show that the nanosized micelles were estimated with a size of 161±10 nm,a polydispersity index of 0.09,a surface charge of-20.3±1.4 mV and the nanosized micelles were spherical and uniform in size.The stability of nanosized micelles after crosslinking were stable against large volume dilution and concentrated salt condition.But in the GSH,the size of the nanosized micelles was increased due to the destruction of the micelles structure.When used for load DOX,the carrier loading efficiency and entrapment efficiency were 10.4%and 58.9%.In vitro drug release studies showed that the cross-linked DOX-loaded nanosized micelles had a reduced response to the release of doxorubicin:only 20.4%DOX was released from DOX-loaded crosslinked nanosized micelles,after 12 hours in 10 mM PBS.However,85.2%DOX was released in 12 hours in the presence of 10 mM GSH(mimicking the intracelullar reductive environment)under otherwise the same conditions.Toxicity studies demonstrated that the cross-linked DOX-loaded nanosized micelles had lower cytotoxicity,it not only retain the high cytotoxicity of the DOX itself,but also reduce the damage to normal cells,showing a good dose-dependent.It has also been shown that the carrier itself is non-toxic.In the next work,a biodegradable polymer-drug conjugate of doxorubicin(DOX)conjugated to the biocompatible hydrophilic dextran(Dex)through redox-responsive cleavable disulfide bonds.The obtained polymer-drug conjugate Dex-SS-DOX could self-assemble into DOX-loaded nanosized micelles in aqueous medium with a low critical micelle concentration.The size of the micelles was 177±10 nm with a narrow size distribution,a polydispersity index of 0.09,a surface charge of around-30.1±1.2 mV.The DOX release behavior of DOX-loaded nanosized micelles was investigated,the cumulative release rate of DOX in PBS was 20.2%?23.4%and 23.5,the cumulative release rate of DOX in GSH was 48.9%?78.3%and 81.4%,which indicated that the micelles had good reduction response.Toxicity studies have shown that nanosized micelles are effective in suppressing cancer cells while not causing significant side effects on normal cells.In conclusion,the drug carrier in this paper designed to achieve reduction response to tumor microenvironment?... |
PDF Full Text Request