title: Antitumor efficacy and tolerability of systemically administered gallium acetylacetonate-loaded gelucire-stabilized nanoparticles.
abstract: The widespread clinical success with most gallium compounds in cancer therapy is markedly hampered by lack of tumor specific accumulation, poor tumor permeability and undesirable toxicity to healthy tissues. The aim of this work was to investigate for the first time antitumor mechanism of a new gallium compound (gallium acetylacetonate; GaAcAc) while assessing effectiveness of gelucire-stabilized nanoparticles (NPs) for potential application in gallium-based lung cancer therapy. NPs loaded with GaAcAc (Ga-NPs) were prepared using mixtures of cetyl alcohol with Gelucire 44/14 (Ga-NP-1) or Gelucire 53/13 (Ga-NP-2) as matrix materials. Of special note from this work is the direct evidence of involvement of microtubule disruption in antitumor effects of GaAcAc on human lung adenocarcinoma (A549). In-vivo tolerability studies were based on plasma ALT, creatinine levels and histopathological examination of tissues. The superior in-vivo antitumor efficacy of Ga-NPs over GaAcAc was depicted in marked reduction of tumor weight and tumor volume as well as histological assessment of excised tumors. Compared to free GaAcAc, Ga-NPs showed a 3-fold increase in tumor-to-blood gallium concentrations with minimized overall exposure to healthy tissues. Overall, enhancement of antitumor effects of GaAcAc by gelucire-stabilized NPs coupled with reduced exposure of healthy tissues to gallium would likely ensure desired therapeutic outcomes and safety of gallium-based cancer treatment.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy Northeast Ohio Medical University, Rootstown, OH 44272, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Wehrung
authors.forename: Lipeng
authors.initials: L
authors.lastname: Bi
authors.forename: Werner J
authors.initials: WJ
authors.lastname: Geldenhuys
authors.forename: Moses O
authors.initials: MO
authors.lastname: Oyewumi
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004355:Drug Stability; D004361:Drug Tolerance; D005708:Gallium / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity*; D006801:Humans; D007928:Lethal Dose 50; D008657:Metabolic Clearance Rate; D051379:Mice; D008819:Mice, Nude; D053769:Nanocapsules / Q000008:administration & dosage* / Q000737:chemistry / Q000633:toxicity*; D009928:Organ Specificity; D014018:Tissue Distribution; D016896:Treatment Outcome; D014280:Triglycerides / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D053769:Nanocapsules; D014280:Triglycerides; C507309:gelucire 43-01; D005708:Gallium