Antitumor effect of novel gallium compounds and efficacy of nanoparticle-mediated gallium delivery in lung cancer.
Antineoplastic Agents/*administration & dosage/chemistry/pharmacokinetics; Biocompatible Materials/administration & dosage/chemistry/pharmacokinetics; Cell Line; Cell Survival/drug effects; Coordination Complexes/*administration & dosage/chemistry/pharmacokinetics; Drug Carriers/administration & dosage/chemistry; Drug Stability; Endocytosis/drug effects; Gallium/*administration & dosage/chemistry/pharmacokinetics; Hemolysis/drug effects; Humans; Lung Neoplasms/*drug therapy/metabolism; Materials Testing; Membrane Potential; Mitochondrial/drug effects; Nanoparticles/*administration & dosage/chemistry; Particle Size; Platelet Aggregation/drug effects; Reactive Oxygen Species/metabolism; Transferrin/chemistry/pharmacology; Tumor
The widespread application of gallium (Ga) in cancer therapy has been greatly hampered by lack of specificity resulting in poor tumor accumulation and retention. To address the challenge, two lipophilic gallium (III) compounds (gallium hexanedione; GaH and gallium acetylacetonate; GaAcAc) were synthesized and antitumor studies were conducted in human lung adenocarcinoma (A549) cells. Nanoparticles (NPs) containing various concentrations of the Ga compounds were prepared using a binary mixture of Gelucire 44/14 and cetyl alcohol as matrix materials. NPs were characterized based on size, morphology, stability and biocompatibility. Antitumor effects of free or NP-loaded Ga compounds were investigated based on cell viability, production of reactive oxygen species and reduction of mitochondrial potential. Compared to free Ga compounds, cytotoxicity of NP-loaded Ga (5-150 microg/ml) was less dependent on concentration and incubation time (exposure) with A549 cells. NP-mediated delivery (5-150 microg Ga/ml) enhanced antitumor effects of Ga compounds and the effect was pronounced at: (i) shorter incubation times; and (ii) at low concentrations of gallium (approximately 50 microg/ml) (p \textless 0.0006). Additional studies showed that
Wehrung Daniel; Oyewumi Moses O
Journal of biomedical nanotechnology
2012
2012-02
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1166/jbn.2012.1361" target="_blank" rel="noreferrer noopener">10.1166/jbn.2012.1361</a>
Antitumor efficacy and tolerability of systemically administered gallium acetylacetonate-loaded gelucire-stabilized nanoparticles.
*Lethal Dose 50; Adenocarcinoma/*drug therapy/pathology; Animals; Antineoplastic Agents/administration & dosage/pharmacokinetics/toxicity; Cell Line; Dose-Response Relationship; Drug; Drug Stability; Drug Tolerance; Gallium/*administration & dosage/pharmacokinetics/*toxicity; Humans; Metabolic Clearance Rate; Mice; Nanocapsules/*administration & dosage/chemistry/*toxicity; Nude; Organ Specificity; Tissue Distribution; Treatment Outcome; Triglycerides/chemistry; Tumor
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.
Wehrung Daniel; Bi Lipeng; Geldenhuys Werner J; Oyewumi Moses O
Journal of biomedical nanotechnology
2013
2013-06
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1166/jbn.2013.1598" target="_blank" rel="noreferrer noopener">10.1166/jbn.2013.1598</a>