title: Improved antitumor effect of paclitaxel administered in vivo as pH and glutathione-sensitive nanohydrogels.
abstract: Most antitumor drugs usually affect not only rapidly dividing cells, such as those in tumors, but also highly proliferative cells in normal tissues. This nonspecific drawback could be successfully solved by using nanocarriers as controlled drug delivery systems. In this work, pH and redox-responsive nanohydrogels (NG) based on N-isopropylacrilamide (NIPA), N-hydroxyethyl acrylamide (HEEA) 2-acrylamidoethyl carbamate (2AAECM) and N,N'-cystaminebisacrylamide (CBA) as crosslinker were evaluated as bioreducible paclitaxel (PTX) nanocarriers for improving the accumulation of the drug within the tumor tissue and avoiding its conventional side effects. A single dose of PTX solution, unloaded-NHA 80/15/5CBA NG and PTX-loaded NHA 80/15/5-CBA NG (30 mg/kg PTX equivalent) were subcutaneously injected in female athymic nude mice bearing HeLa human tumor xenografts. PTX-loaded nanohydrogels showed higher antitumor activity than free PTX, as tumor evolution and Ki67 detection demonstrated. Histological tumor images revealed a higher content of defective mitotic figures and apoptotic bodies in PTX- treated tumors than in control or unloaded NG treated tumor samples. Nanohydrogels injection did not change any biochemical blood parameters, which means no liver or kidney damage after NG injection. However, differences in antioxidant defenses in MPS systems (liver, kidney and spleen) were observed among treatments, which may indicate an oxidative stress response after PTX injection.
authors.affiliation: Dpto. Bioquímica y Biología Molecular III, Facultad de Medicina, Ciudad Universitaria s/n, UCM, 28040 Madrid, Spain. Electronic address: elenpe01@ucm.es.
authors.forename: Elena
authors.initials: E
authors.lastname: Pérez
authors.affiliation: Facultad de Farmacia, Universidad Francisco de Vitoria, Madrid, Spain. Electronic address: am.martinez.prof@ufv.es.
authors.forename: Ana
authors.initials: A
authors.lastname: Martínez
authors.affiliation: Dpto. Enfermería, Facultad de Enfermería, Fisioterapia y Podología, Ciudad Universitaria s/n, UCM, 28040 Madrid, Spain. Electronic address: cteijon@enf.ucm.es.
authors.forename: César
authors.initials: C
authors.lastname: Teijón
authors.affiliation: Dpto. Bioquímica y Biología Molecular III, Facultad de Medicina, Ciudad Universitaria s/n, UCM, 28040 Madrid, Spain. Electronic address: rmolmo@med.ucm.es.
authors.forename: Rosa
authors.initials: R
authors.lastname: Olmo
authors.affiliation: Dpto. Bioquímica y Biología Molecular III, Facultad de Medicina, Ciudad Universitaria s/n, UCM, 28040 Madrid, Spain. Electronic address: jmt@med.ucm.es.
authors.forename: José María
authors.initials: JM
authors.lastname: Teijón
authors.affiliation: Dpto. Bioquímica y Biología Molecular III, Facultad de Medicina, Ciudad Universitaria s/n, UCM, 28040 Madrid, Spain. Electronic address: mdblanco@med.ucm.es.
authors.forename: María Dolores
authors.initials: MD
authors.lastname: Blanco
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D002374:Catalase / Q000378:metabolism; D005260:Female; D005978:Glutathione / Q000378:metabolism; D019803:Glutathione Disulfide / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D020100:Hydrogels / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D006863:Hydrogen-Ion Concentration; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008819:Mice, Nude; D049329:Nanostructures / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D013154:Spleen / Q000187:drug effects / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D020100:Hydrogels; D002374:Catalase; D013482:Superoxide Dismutase; D005978:Glutathione; D017239:Paclitaxel; D019803:Glutathione Disulfide
keywords: Anti-tumor efficacy; Histopathology; In vivo toxicity; Oxidative stress; Paclitaxel; Stimuli responsive nanohydrogel