title: Polymeric Micelle-Mediated Delivery of DNA-Targeting Organometallic Complexes for Resistant Ovarian Cancer Treatment.
abstract: Three half-sandwich iridium and ruthenium organometallic complexes with high cytotoxicity are synthesized, and their anticancer mechanisms are elucidated. The organometallic complexes can interact with DNA through coordination or intercalation, thereby inducing apoptosis and inhibiting proliferation of resistant cancer cells. The organometallic complexes are then incorporated into polymeric micelles through the polymer-metal coordination between poly(ethylene glycol)-b-poly(glutamic acid) [PEG-b-P(Glu)] and organometallic complexes to further enhance their anticancer effects as a result of the enhanced permeability and retention effect. The micelles with particle sizes of ≈60 nm are more efficiently internalized by cancer cells than the corresponding complexes, and selectively dissociate and release organometallic anticancer agents within late endosomes and lysosomes, thereby enhancing drug delivery to the nuclei of cancer cells and facilitating their interactions with DNA. Thus, the micelles display higher antitumor activity than the organometallic complexes alone with a lack of the systemic toxicity in a mouse xenograft model of cisplatin-resistant human ovarian cancer. These results suggest that the polymeric micelles carrying anticancer organometallic complexes provide a promising platform for the treatment of resistant ovarian cancer and other hard-to-treat solid tumors.
authors.affiliation: Department of Chemistry, University of Chicago, 929 E 57th St, Chicago, IL, 60637, USA.
authors.forename: Xiaopin
authors.initials: X
authors.lastname: Duan
authors.affiliation: Department of Chemistry, University of Chicago, 929 E 57th St, Chicago, IL, 60637, USA.
authors.forename: Demin
authors.initials: D
authors.lastname: Liu
authors.affiliation: Department of Chemistry, University of Chicago, 929 E 57th St, Chicago, IL, 60637, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Chan
authors.affiliation: Department of Chemistry, University of Chicago, 929 E 57th St, Chicago, IL, 60637, USA.
authors.forename: Wenbin
authors.initials: W
authors.lastname: Lin
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001835:Body Weight / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D004247:DNA / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D008819:Mice, Nude; D008823:Micelles; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011108:Polymers / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D008823:Micelles; D009942:Organometallic Compounds; D011108:Polymers; D004247:DNA
keywords: DNA targeting; drug delivery; organometallic complexes; ovarian cancers; polymeric micelles