Tumor-targeting nanodelivery enhances the anticancer activity of a novel quinazolinone analogue.
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.
Hwang
Sung Hee
SH
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057-1469, USA.
Rait
Antonina
A
Pirollo
Kathleen F
KF
Zhou
Qi
Q
Yenugonda
Venkata Mahidhar
VM
Chinigo
Gary M
GM
Brown
Milton L
ML
Chang
Esther H
EH
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*
D000970:Antineoplastic Agents; D052999:Quinazolinones