title: Stepwise targeted drug delivery to liver cancer cells for enhanced therapeutic efficacy by galactose-grafted, ultra-pH-sensitive micelles.
abstract: To promote drug accumulation and cell-killing ability at tumor tissue, we have prepared a stepwise targeted drug delivery system that can remain stealthy and long-circulating in the blood vessels, improve drug retention at extracellular stimuli, enhance cellular uptake through special targeting ligands, and then achieve rapid drug release to improve toxicity to tumor cells at intracellular stimuli. Herein, galactose-grafted, ultra-pH-sensitive drug carriers (POEAd-g-LA-DOX micelles), which could respond to both extracellular and intracellular pH, and combine with galactose-receptors in cell membrane, were constructed by a facile method, therefore achieving: (i) remaining stable at pH 7.4; (ii) responding to tumoral extracellular pH following gradually larger nanoparticles (NPs); (iii) conjugating receptors in the cell membrane of liver cancer through surface galactose-ligands of micelles; (iv) being sensitive to tumoral intracellular pH following further swelling for rapid drug release. In vitro cytotoxicity and cellular uptake measurement showed that POEAd-g-LA20-DOX micelle was more easily internalized and more toxic effect on tumor cells than free DOX. Moreover, in vivo biodistribution and tumor inhibition examinations demonstrated that POEAd-g-LA20-DOX formulation had more superior efficacy to significantly enhance drug accumulation in tumor, and then restrain tumor growth while decreasing drug concentration in heart.
  
  
  
  Chemotherapeutic efficacy is limited by poor tumor selectivity, which also causes severe toxicity in normal tissues and organs, although many targeted drug delivery systems have been developed by passive targeting strategies or active targeting strategies with specific targeting ligands in recent years. Herein, galactose-grafted, ultra-pH-sensitive, ortho ester-based drug carriers, which can respond to both extracellular and intracellular pH, and target to galactose-receptors in cell membrane, have been successfully constructed by facile method, therefore achieving stepwise targeting to microenvironment of liver cancer and then enhancing drug accumulation and tumor inhibition. The strategy of designing dual-stimuli-responsive copolymers can be potentially useful, and extrapolated to synthesizing other categories of highly labile drug carriers in a range of biomedical applications.
authors.affiliation: Engineering Research Center for Biomedical Materials, School of Life Science, Anhui University, 111 Jiulong Road, Hefei, Anhui Province 230601, PR China.
authors.forename: Guoqing
authors.initials: G
authors.lastname: Yan
authors.affiliation: Engineering Research Center for Biomedical Materials, School of Life Science, Anhui University, 111 Jiulong Road, Hefei, Anhui Province 230601, PR China.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.affiliation: Engineering Research Center for Biomedical Materials, School of Life Science, Anhui University, 111 Jiulong Road, Hefei, Anhui Province 230601, PR China.
authors.forename: Liefeng
authors.initials: L
authors.lastname: Hu
authors.affiliation: Engineering Research Center for Biomedical Materials, School of Life Science, Anhui University, 111 Jiulong Road, Hefei, Anhui Province 230601, PR China.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Engineering Research Center for Biomedical Materials, School of Life Science, Anhui University, 111 Jiulong Road, Hefei, Anhui Province 230601, PR China.
authors.forename: Guanqing
authors.initials: G
authors.lastname: Yang
authors.affiliation: Engineering Research Center for Biomedical Materials, School of Life Science, Anhui University, 111 Jiulong Road, Hefei, Anhui Province 230601, PR China.
authors.forename: Shengxiang
authors.initials: S
authors.lastname: Fu
authors.affiliation: Engineering Research Center for Biomedical Materials, School of Life Science, Anhui University, 111 Jiulong Road, Hefei, Anhui Province 230601, PR China.
authors.forename: Xu
authors.initials: X
authors.lastname: Cheng
authors.affiliation: Engineering Research Center for Biomedical Materials, School of Life Science, Anhui University, 111 Jiulong Road, Hefei, Anhui Province 230601, PR China.
authors.forename: Panpan
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Engineering Research Center for Biomedical Materials, School of Life Science, Anhui University, 111 Jiulong Road, Hefei, Anhui Province 230601, PR China. Electronic address: tangrp99@iccas.ac.cn.
authors.forename: Rupei
authors.initials: R
authors.lastname: Tang
mesh_terms: D000818:Animals; D016923:Cell Death; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004187:Disaccharides / Q000737:chemistry; D004317:Doxorubicin / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D016503:Drug Delivery Systems / Q000379:methods*; D065546:Drug Liberation; D000067493:Dynamic Light Scattering; D005690:Galactose / Q000737:chemistry*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D007700:Kinetics; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008823:Micelles; D010316:Particle Size; D011108:Polymers / Q000737:chemistry; D066244:Proton Magnetic Resonance Spectroscopy; D014018:Tissue Distribution / Q000187:drug effects; D016896:Treatment Outcome
chemical_list: D004187:Disaccharides; D008823:Micelles; D011108:Polymers; C005608:lactobionic acid; D004317:Doxorubicin; D005690:Galactose
keywords: Antitumor; Lactobionic acid; Micelles; Ortho ester; pH-sensitivity