title: Encapsulation of the flavonoid quercetin with an arsenic chelator into nanocapsules enables the simultaneous delivery of hydrophobic and hydrophilic drugs with a synergistic effect against chronic arsenic accumulation and oxidative stress.
abstract: Chronic arsenic exposure causes oxidative stress and mitochondrial dysfunction in the liver and brain. The ideal treatment would be to chelate arsenic and prevent oxidative stress. meso-2,3-Dimercaptosuccinic acid (DMSA) is used to chelate arsenic but its hydrophilicity makes it membrane-impermeative. Conversely, quercetin (QC) is a good antioxidant with limited clinical application because of its hydrophobic nature and limited bioavailability, and it is not possible to solubilize these two compounds in a single nontoxic solvent. Nanocapsules have emerged as a potent drug delivery system and make it feasible to incorporate both hydrophilic and lipophilic compounds. Nanoencapsulated formulations with QC and DMSA either alone or coencapsulated in polylactide-co-glycolide [N(QC+DMSA)] were synthesized to explore their therapeutic application in a rat model of chronic arsenic toxicity. These treatments were compared to administration of quercetin or DMSA alone using conventional delivery methods. Both nanoencapsulated quercetin and nanoencapsulated DMSA were more effective at decreasing oxidative injury in liver or brain compared to conventional delivery methods, but coencapsulation of quercetin and DMSA into nanoparticles had a marked synergistic effect, decreasing liver and brain arsenic levels from 9.5 and 4.8μg/g to 2.2 and 1.5μg/g, respectively. Likewise, administration of coencapsulated quercetin and DMSA virtually normalized changes in mitochondrial function, formation of reactive oxygen species, and liver injury. We conclude that coencapsulation of quercetin and DMSA may provide a more effective therapeutic strategy in the management of arsenic toxicity and also presents a novel way of combining hydrophilic and hydrophobic drugs into a single delivery system.
authors.affiliation: Biomembrane Division, Indian Institute of Chemical Biology, Kolkata 700032, India.
authors.forename: Swarupa
authors.initials: S
authors.lastname: Ghosh
authors.forename: Sandhya Rekha
authors.initials: SR
authors.lastname: Dungdung
authors.forename: Somsubhra Thakur
authors.initials: ST
authors.lastname: Chowdhury
authors.forename: Ardhendu K
authors.initials: AK
authors.lastname: Mandal
authors.forename: Sibani
authors.initials: S
authors.lastname: Sarkar
authors.forename: Debasree
authors.initials: D
authors.lastname: Ghosh
authors.forename: Nirmalendu
authors.initials: N
authors.lastname: Das
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage; D001151:Arsenic / Q000378:metabolism*; D020261:Arsenic Poisoning / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002614:Chelating Agents / Q000008:administration & dosage; D004195:Disease Models, Animal; D004339:Drug Compounding / Q000379:methods; D016503:Drug Delivery Systems; D004357:Drug Synergism; D005260:Female; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D019344:Lactic Acid / Q000737:chemistry; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D053758:Nanoparticles / Q000737:chemistry / Q000627:therapeutic use*; D018384:Oxidative Stress / Q000187:drug effects; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011794:Quercetin / Q000008:administration & dosage; D051381:Rats; D017208:Rats, Wistar; D004113:Succimer / Q000008:administration & dosage
chemical_list: D000975:Antioxidants; D002614:Chelating Agents; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D011794:Quercetin; D004113:Succimer; D001151:Arsenic