Vascular-confined multi-passage discoidal nanoconstructs for the low-dose docetaxel inhibition of triple-negative breast cancer growth  

作　　者：Alessia Felici Daniele Di Mascolo Miguel Ferreira Simone Lauciello Luca Bono Andrea Armirotti Arunkumar Pitchaimani Anna Lisa Palange Paolo Decuzzi 

机构地区：[1]Laboratory of Nanotechnology for Precision Medicine,Fondazione Istituto Italiano di Tecnologia,Genoa 16163,Italy [2]Department of Informatics,Bioengineering,Robotics and System Engineering,University of Genoa,Genoa 16126,Italy [3]Nanochemistry Laboratory,Fondazione Istituto Italiano di Tecnologia,Genoa 16163,Italy [4]Analytical Chemistry Laboratory,Fondazione Istituto Italiano di Tecnologia,Genoa 16163,Italy

出　　处：《Nano Research》2022年第1期482-491,共10页纳米研究（英文版）

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.

摘　　要：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.

关 键 词：hydrogel particles template strategy vascular targeting biomimicry cancer therapy 

分 类 号：R73[医药卫生—肿瘤] R318[医药卫生—临床医学]