Tumor-targeting nanodelivery enhances the anticancer activity of a novel quinazolinone analogue

• Published in: Molecular cancer therapeutics 2008-03, Vol.7 (3), p.559-568
• Main Authors: Hwang, Sung Hee, Rait, Antonina, Pirollo, Kathleen F, Zhou, Qi, Yenugonda, Venkata Mahidhar, Chinigo, Gary M, Brown, Milton L, Chang, Esther H
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - administration & dosage; Antineoplastic Agents - chemistry; Antineoplastic Agents - therapeutic use; cancer treatment; Cell Line, Tumor; chemosensitization; Drug Delivery Systems; GMC-5-193; Humans; Male; Molecular Structure; nanocomplex; Nanotechnology; Quinazolinones - administration & dosage; Quinazolinones - chemistry; Quinazolinones - therapeutic use; tumor targeting
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-07-0548

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 ∼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. [Mol Cancer Ther 2008;7(3):559–68]