title: Lipid encapsulation of arsenic trioxide attenuates cytotoxicity and allows for controlled anticancer drug release.
abstract: Arsenic trioxide (ATO, As2O3) is emerging as a front line agent for treatment of acute promyelocytic leukemia with giving a complete remission rate of 83-95%. ATO also shows significant activity in relapsed/refactory multiple myeloma; however, efforts to expand clinical utility to other cancers have been limited by its toxicity profile at higher doses. New bioavailable, liposome encapsulated As(III) materials exhibit a significantly attenuated cytotoxicity that undergoes pH-triggered release of an active drug. The arsenic drugs are loaded into 100-nm-scale liposomes at high concentration (>270 mM) and excellent retention (shelf life > 6 months at 4 degrees C), as determined by inductively coupled plasma optical emission spectroscopy (ICP-OES), transmission electron microscopy (TEM), and energy-dispersive X-ray (EDX) diffraction. In the loading mechanism, arsenous acid crosses the bilayer membrane in exchange for acetic acid and an insoluble transitional metal (e.g., Ni2+, Co2+) arsenite salt is formed. The resultant liposomal arsenic nanoparticles appear to be stable in physiological situations but release the drug cargo in a lower pH environment, as encountered in intracellular endosomes. These drugs exhibit attenuated cytotoxicities against human lymphoma tumor cells compared with that of free As2O3. Controlled release of arsenic drugs, and hence control of toxicity, is feasible with this system. The results demonstrate that cytotoxicity can be controlled via transitions of the inorganic drug between solid and solution phases and suggest a mechanism for further improvement of the risk/benefit ratio of As2O3 in treatment of a variety of cancers.
authors.affiliation: Department of Chemistry, Northwestern University, Evanston, IL 60208, USA.
authors.forename: Haimei
authors.initials: H
authors.lastname: Chen
authors.forename: Robert C
authors.initials: RC
authors.lastname: MacDonald
authors.forename: Shuyou
authors.initials: S
authors.lastname: Li
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Krett
authors.forename: Steven T
authors.initials: ST
authors.lastname: Rosen
authors.forename: Thomas V
authors.initials: TV
authors.lastname: O'Halloran
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000008:administration & dosage* / Q000494:pharmacology; D002214:Capsules / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D004317:Doxorubicin / Q000494:pharmacology; D016503:Drug Delivery Systems; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008055:Lipids / Q000737:chemistry*; D008081:Liposomes / Q000737:chemistry*; D008214:Lymphocytes / Q000187:drug effects / Q000473:pathology; D046529:Microscopy, Electron, Transmission; D010087:Oxides / Q000008:administration & dosage* / Q000494:pharmacology; D013696:Temperature; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D001152:Arsenicals; D002214:Capsules; D008055:Lipids; D008081:Liposomes; D010087:Oxides; D004317:Doxorubicin; D000077237:Arsenic Trioxide