title: Dexamethasone-loaded block copolymer nanoparticles induce leukemia cell death and enhance therapeutic efficacy: a novel application in pediatric nanomedicine.
abstract: Nanotechnology approaches have tremendous potential for enhancing treatment efficacy with lower doses of chemotherapeutics. Nanoparticle (NP)-based drug delivery approaches are poorly developed for childhood leukemia. Dexamethasone (Dex) is one of the most common chemotherapeutic drugs used in the treatment of childhood leukemia. In this study, we encapsulated Dex in polymeric NPs and validated their antileukemic potential in vitro and in vivo. NPs with an average diameter of 110 nm were assembled from an amphiphilic block copolymer of poly(ethylene glycol) (PEG) and poly(ε-caprolactone) (PCL) bearing pendant cyclic ketals (ECT2). The blank NPs were nontoxic to cultured cells in vitro and to mice in vivo. Encapsulation of Dex into the NPs (Dex-NP) did not compromise the bioactivity of the drug. Dex-NPs induced glucocorticoid phosphorylation and showed cytotoxicity similar to the free Dex in leukemic cells. Studies using NPs labeled with fluorescent dyes revealed leukemic cell surface binding and internalization. In vivo biodistribution studies showed NP accumulation in the liver and spleen with subsequent clearance of the particles with time. In a preclinical model of leukemia, Dex-NPs significantly improved the quality of life and survival of mice as compared to the free drug. To our knowledge, this is the first report showing the efficacy of polymeric NPs to deliver Dex to potentially treat childhood leukemia and reveals that low doses of Dex should be sufficient for inducing cell death and improving survival.
authors.affiliation: Department of Materials Science and Engineering, University of Delaware, Newark, Delaware 19716-1501, USA.
authors.forename: Vinu
authors.initials: V
authors.lastname: Krishnan
authors.forename: Xian
authors.initials: X
authors.lastname: Xu
authors.forename: Sonali P
authors.initials: SP
authors.lastname: Barwe
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Yang
authors.forename: Kirk
authors.initials: K
authors.lastname: Czymmek
authors.forename: Scott A
authors.initials: SA
authors.lastname: Waldman
authors.forename: Robert W
authors.initials: RW
authors.lastname: Mason
authors.forename: Xinqiao
authors.initials: X
authors.lastname: Jia
authors.forename: Ayyappan K
authors.initials: AK
authors.lastname: Rajasekaran
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003907:Dexamethasone / Q000737:chemistry* / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007938:Leukemia / Q000188:drug therapy*; D008099:Liver / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D050997:Nanomedicine / Q000379:methods*; D053758:Nanoparticles / Q000737:chemistry*; D010766:Phosphorylation / Q000187:drug effects; D011091:Polyesters / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D011108:Polymers / Q000737:chemistry*; D013154:Spleen / Q000378:metabolism
chemical_list: D011091:Polyesters; D011108:Polymers; D011092:Polyethylene Glycols; D003907:Dexamethasone