Taxane efficacy in triple negative breast cancer(TNBC)is limited by insufficient tumor accumulation and severe off-target effects.Nanomedicines offer a unique opportunity to enhance the anti-cancer potency of this dru...Taxane efficacy in triple negative breast cancer(TNBC)is limited by insufficient tumor accumulation and severe off-target effects.Nanomedicines offer a unique opportunity to enhance the anti-cancer potency of this drug.Here,1,000 nm×400 nm discoidal polymeric nanoconstructs(DPN)encapsulating docetaxel(DTXL)and the near infrared compound Iipid-Cy5 were engineered.DPN were obtained by filling multiple times cylindrical wells in a poly(vinyl alcohol)template with a polymer mixture comprising poly(lactic-co-glycolic acid)(PLGA)and poly(ethylene glycol)diacrylate(PEG-DA)chains together with therapeutic and imaging agents.The resulting“multi-passage”DPN exhibited higher DTXL loading,Iipid-Cy5 stability,and stiffness as compared to the conventional"single-passage"approach.Confocal microscopy confirmed that DTXL-DPN were not taken up by MDA-MB-231 cells but would rather sit next to the cell membrane and slowly release DTXL thereof.Empty DPN had no toxicity on TNBC cells,whereas DTXL-DPN presented a cytotoxic potential comparable to free DTXL(IC_(50)=2.6 nM±1.0 nM vs.7.0 nM±1.09 nM at 72 h).In orthotopic murine models,DPN accumulated in TNBC more efficiently than free-DTXL.With only 2 mg/kg DTXL,intravenously administered every 2 days for a total of 13 treatments,DTXL-DPN induced tumor regression and were associated to an overall 80%survival rate as opposed to a 30%survival rate for free-DTXL,at 120 days.All untreated mice succumbed before 90 days.Collectively,this data demonstrates that vascular confined multi-passage DPN,biomimicking the behavior of circulating platelets,can efficiently deliver chemotherapeutic molecules to malignant tissues and effectively treat orthotopic TNBC at minimal taxane doses.展开更多
基金supported by the European Research Council,under the European Unions Seventh Framework Programme(FP7/2007-2013)/ERC grant agreement No.616695,by the Italian Association for Cancer Research(AIRC)under the individual investigator grant No.17664,and by the European Unions Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No.754490.
文摘Taxane efficacy in triple negative breast cancer(TNBC)is limited by insufficient tumor accumulation and severe off-target effects.Nanomedicines offer a unique opportunity to enhance the anti-cancer potency of this drug.Here,1,000 nm×400 nm discoidal polymeric nanoconstructs(DPN)encapsulating docetaxel(DTXL)and the near infrared compound Iipid-Cy5 were engineered.DPN were obtained by filling multiple times cylindrical wells in a poly(vinyl alcohol)template with a polymer mixture comprising poly(lactic-co-glycolic acid)(PLGA)and poly(ethylene glycol)diacrylate(PEG-DA)chains together with therapeutic and imaging agents.The resulting“multi-passage”DPN exhibited higher DTXL loading,Iipid-Cy5 stability,and stiffness as compared to the conventional"single-passage"approach.Confocal microscopy confirmed that DTXL-DPN were not taken up by MDA-MB-231 cells but would rather sit next to the cell membrane and slowly release DTXL thereof.Empty DPN had no toxicity on TNBC cells,whereas DTXL-DPN presented a cytotoxic potential comparable to free DTXL(IC_(50)=2.6 nM±1.0 nM vs.7.0 nM±1.09 nM at 72 h).In orthotopic murine models,DPN accumulated in TNBC more efficiently than free-DTXL.With only 2 mg/kg DTXL,intravenously administered every 2 days for a total of 13 treatments,DTXL-DPN induced tumor regression and were associated to an overall 80%survival rate as opposed to a 30%survival rate for free-DTXL,at 120 days.All untreated mice succumbed before 90 days.Collectively,this data demonstrates that vascular confined multi-passage DPN,biomimicking the behavior of circulating platelets,can efficiently deliver chemotherapeutic molecules to malignant tissues and effectively treat orthotopic TNBC at minimal taxane doses.
