title: Tumor-targeting nanodelivery enhances the anticancer activity of a novel quinazolinone analogue.
abstract: GMC-5-193 (GMC) is a novel anticancer small-molecule quinazolinone analogue with properties that include antimicrotubule activity and inherent fluorescence. The aim of this study was to produce and optimize a systemically administered liposomal formulation for tumor-targeting delivery of GMC to enhance the anticancer effect of this compound and evaluate its bioefficacy. GMC was encapsulated within a cationic liposome, which was decorated on the surface with an anti-transferrin receptor single-chain antibody fragment (TfRscFv) as the tumor-targeting moiety to form a nanoscale complex (scL/GMC). Confocal imaging of fluorescent GMC uptake in a human melanoma cell line, MDA-MB-435, showed higher cellular uptake of GMC when delivered via the liposome complex compared with free GMC. Delivery of GMC by the tumor-targeting liposome nanoimmunocomplex also resulted in a 3- to 4-fold decrease in IC(50) values in human cancer cells [DU145 (prostate) and MDA-MB-435] compared with the effects of GMC administered as free GMC. In addition, the GMC nanoimmunocomplex increased the sensitivity of cancer cells to doxorubicin, docetaxel, or mitoxantrone by approximately 3- to 30-fold. In the MDA435/LCC6 athymic nude mice xenograft lung metastases model, GMC was specifically delivered to tumors by the nanoimmunocomplex. These data show that incorporation of small-molecule therapeutic GMC within the tumor-targeting liposome nanocomplex enhances its anticancer effect.
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057-1469, USA.
authors.forename: Sung Hee
authors.initials: SH
authors.lastname: Hwang
authors.forename: Antonina
authors.initials: A
authors.lastname: Rait
authors.forename: Kathleen F
authors.initials: KF
authors.lastname: Pirollo
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhou
authors.forename: Venkata Mahidhar
authors.initials: VM
authors.lastname: Yenugonda
authors.forename: Gary M
authors.initials: GM
authors.lastname: Chinigo
authors.forename: Milton L
authors.initials: ML
authors.lastname: Brown
authors.forename: Esther H
authors.initials: EH
authors.lastname: Chang
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D006801:Humans; D008297:Male; D015394:Molecular Structure; D036103:Nanotechnology; D052999:Quinazolinones / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D052999:Quinazolinones