TPGS approved by FDA can be used as a P-gp inhibitor to effectively reverse multi-drug resistance(MDR)and as an anticancer agent for synergistic antitumor effects.However,the comparatively high critical micelle concen...TPGS approved by FDA can be used as a P-gp inhibitor to effectively reverse multi-drug resistance(MDR)and as an anticancer agent for synergistic antitumor effects.However,the comparatively high critical micelle concentration(CMC),low drug loading(DL)and poor tumor target limit its further clinical application.To overcome these drawbacks,the pH-sensitive star-shaped TPGS copolymers were successfully constructed via using pentaerythritol as the initial materials,ortho esters as the pH-triggered linkages and TPGS active-ester as the terminated MDR material.The amphiphilic star-shaped TPGS copolymers could self-assemble into free and doxorubicin(DOX)-loaded micelles at neutral aqueous solutions.The micelles exhibited the lower CMC(8.2×10^(−5) mg/ml),higher DL(10.8%)and long-term storage and circulation stability,and showed enhanced cellular uptake,apoptosis,cytotoxicity,and growth inhibition for in vitro MCF-7/ADR and/or MCF-7/ADR multicellular spheroids and in vivo MCF-7/ADR tumors via efficiently targeted drug release at tumoral intracellular pH(5.0),MDR reversal of TPGS,and synergistic effect of DOX and TPGS.Therefore,the pH-sensitive micelles self-assembled from star-shaped TPGS copolymers with ortho ester linkages are potentially useful to clinically transform for enhanced MDR cancer treatment.展开更多
A novel β-cyclodextrin-poly（2-（2-methoxyethoxy）ethyl methacrylate）-co- poly（ethylene glycol） methacrylate （abbreviated as： β-CD-（P（MEO2MA-co-PEGMA））21） was prepared by using the one-step strategy, and t...A novel β-cyclodextrin-poly（2-（2-methoxyethoxy）ethyl methacrylate）-co- poly（ethylene glycol） methacrylate （abbreviated as： β-CD-（P（MEO2MA-co-PEGMA））21） was prepared by using the one-step strategy, and then the star-shaped copolymers were used in the atom transfer radical polymerization （ATRP）. The structure of star-shaped β- CD-（P（MEO2MA-co-PEGMA））21 copolymers were studied by FTIR, 1H NMR and gel permeation chromatography （GPC）. The star-shaped copolymers could self-assembled into micelles in aqueous solution owing to the outer amphiphilic β-CD as a core and the hydrophilic P（MEO2MA-co-PEGMA） segments as a shell. These thermo-responsive starshaped copolymers micelles exhibited lower critical solution temperature （LCST） in water, which could be finely tuned by changing the feed ratio of MEO2MA to PEGMA. The LCST of star-shaped β-CD-（P（MEO2MA-co-PEGMA））21 copolymer micelles were increased from 35℃ to 58℃ with the increasing content of PEGMA. The results were investigated by DLS and TEM. When the temperature was higher than corresponding LCSTs, the micelles started to associate and form spherical nanoparticles. Therefore, β- CD-（P（MEO2MA-co-PEGMA））21 star-shaped copolymer micelles could be potentially applied in nano-carrier, nano-reactor, smart materials and biomedical fields.展开更多
基金This work is financially supported by the National Natural Science Foundation of China(No.51803001)the Research Foundation of Education Department of Anhui Province of China(No.KJ2018ZD003 and KJ2018A0006)the Academic and Technology Introduction Project of Anhui University(AU02303203).
文摘TPGS approved by FDA can be used as a P-gp inhibitor to effectively reverse multi-drug resistance(MDR)and as an anticancer agent for synergistic antitumor effects.However,the comparatively high critical micelle concentration(CMC),low drug loading(DL)and poor tumor target limit its further clinical application.To overcome these drawbacks,the pH-sensitive star-shaped TPGS copolymers were successfully constructed via using pentaerythritol as the initial materials,ortho esters as the pH-triggered linkages and TPGS active-ester as the terminated MDR material.The amphiphilic star-shaped TPGS copolymers could self-assemble into free and doxorubicin(DOX)-loaded micelles at neutral aqueous solutions.The micelles exhibited the lower CMC(8.2×10^(−5) mg/ml),higher DL(10.8%)and long-term storage and circulation stability,and showed enhanced cellular uptake,apoptosis,cytotoxicity,and growth inhibition for in vitro MCF-7/ADR and/or MCF-7/ADR multicellular spheroids and in vivo MCF-7/ADR tumors via efficiently targeted drug release at tumoral intracellular pH(5.0),MDR reversal of TPGS,and synergistic effect of DOX and TPGS.Therefore,the pH-sensitive micelles self-assembled from star-shaped TPGS copolymers with ortho ester linkages are potentially useful to clinically transform for enhanced MDR cancer treatment.
基金Acknowledgements The authors gratefully acknowledge financial supports from the National Natural Science Foundation of China （Grant No. 51662036） and the Bingtuan Innovation Team in Key Areas （2015BD003）.
文摘A novel β-cyclodextrin-poly（2-（2-methoxyethoxy）ethyl methacrylate）-co- poly（ethylene glycol） methacrylate （abbreviated as： β-CD-（P（MEO2MA-co-PEGMA））21） was prepared by using the one-step strategy, and then the star-shaped copolymers were used in the atom transfer radical polymerization （ATRP）. The structure of star-shaped β- CD-（P（MEO2MA-co-PEGMA））21 copolymers were studied by FTIR, 1H NMR and gel permeation chromatography （GPC）. The star-shaped copolymers could self-assembled into micelles in aqueous solution owing to the outer amphiphilic β-CD as a core and the hydrophilic P（MEO2MA-co-PEGMA） segments as a shell. These thermo-responsive starshaped copolymers micelles exhibited lower critical solution temperature （LCST） in water, which could be finely tuned by changing the feed ratio of MEO2MA to PEGMA. The LCST of star-shaped β-CD-（P（MEO2MA-co-PEGMA））21 copolymer micelles were increased from 35℃ to 58℃ with the increasing content of PEGMA. The results were investigated by DLS and TEM. When the temperature was higher than corresponding LCSTs, the micelles started to associate and form spherical nanoparticles. Therefore, β- CD-（P（MEO2MA-co-PEGMA））21 star-shaped copolymer micelles could be potentially applied in nano-carrier, nano-reactor, smart materials and biomedical fields.
