title: Acid-activatable prodrug nanogels for efficient intracellular doxorubicin release.
abstract: Endosomal pH-activatable doxorubicin (DOX) prodrug nanogels were designed, prepared, and investigated for triggered intracellular drug release in cancer cells. DOX prodrugs with drug grafting contents of 3.9, 5.7, and 11.7 wt % (denoted as prodrugs 1, 2, and 3, respectively) were conveniently obtained by sequential treatment of poly(ethylene glycol)-b-poly(2-hydroxyethyl methacrylate-co-ethyl glycinate methacrylamide) (PEG-b-P(HEMA-co-EGMA)) copolymers with hydrazine and doxorubicin hydrochloride. Notably, prodrugs 1, 2, and 3 formed monodispersed nanogels with average sizes of 114.4, 75.3, and 66.3 nm, respectively, in phosphate buffer (PB, 10 mM, pH 7.4). The in vitro release results showed that DOX was released rapidly and nearly quantitatively from DOX prodrug nanogels at endosomal pH and 37 °C in 48 h, whereas only a minor amount (ca. 20% or less) of drug was released at pH 7.4 under otherwise the same conditions. Confocal laser scanning microscope (CLSM) observations revealed that DOX prodrug nanogels delivered and released DOX into the cytosols as well as cell nuclei of RAW 264.7 cells following 24 h incubation. MTT assays demonstrated that prodrug 3 had pronounced cytotoxic effects to tumor cells following 72 h incubation with IC(50) data determined to be 2.0 and 3.4 μg DOX equiv/mL for RAW 264.7 and MCF-7 tumor cells, respectively. The corresponding polymer carrier, PEG-b-P(HEMA-co-GMA-hydrazide), was shown to be nontoxic up to a tested concentration of 1.32 mg/mL. These endosomal pH-activatable DOX prodrug nanogels uniquely combining features of water-soluble macromolecular prodrugs and nanogels offer a promising platform for targeted cancer therapy.
authors: Biomedical Polymers Laboratory, Department of Polymer Science and Engineering, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, PR China.
authors: Fuxing
authors: F
authors: Zhan
authors: Wei
authors: W
authors: Chen
authors: Zhongjuan
authors: Z
authors: Wang
authors: Wentao
authors: W
authors: Lu
authors: Ru
authors: R
authors: Cheng
authors: Chao
authors: C
authors: Deng
authors: Fenghua
authors: F
authors: Meng
authors: Haiyan
authors: H
authors: Liu
authors: Zhiyuan
authors: Z
authors: Zhong
mesh_terms: D000143:Acids / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000737:chemistry / Q000494:pharmacology*; D004337:Drug Carriers / Q000138:chemical synthesis* / Q000494:pharmacology; D004705:Endocytosis; D011992:Endosomes / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D006834:Hydrazines / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D008264:Macrophages / Q000166:cytology / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008823:Micelles; D058990:Molecular Targeted Therapy / Q000379:methods*; D011092:Polyethylene Glycols / Q000737:chemistry; D011109:Polymethacrylic Acids / Q000737:chemistry; D011355:Prodrugs / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D000143:Acids; D000903:Antibiotics, Antineoplastic; D004337:Drug Carriers; D006834:Hydrazines; D008823:Micelles; C521570:PEG-HEMA; D011109:Polymethacrylic Acids; D011355:Prodrugs; C029424:hydrazine; D011092:Polyethylene Glycols; D004317:Doxorubicin