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Research Articles: Therapeutics, Targets, and Development

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

¹ Department of Oncology and ² Departments of Oncology and Neuroscience, Drug Discovery Program, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, District of Columbia

Requests for reprints: Esther H. Chang, Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, TRB/E420, 3970 Reservoir Road, North West, Washington, DC 20057-1469. Phone: 202-687-8418; Fax: 202-687-8434. E-mail: change{at}georgetown.edu

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 IC₅₀ 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]

Grant support: SynerGene Therapeutics research grant (K.F. Pirollo). These studies were conducted in part using the Microscopy and Imaging, Histopathology and Tissue, and Animal Core Facilities supported by National Cancer Institute Cancer Center Support grant and USPHS grants 2P30-CA-51008 and 1 S10 RR 15768-01. This investigation was conducted in part in a facility constructed with support from Research Facilities Improvement grant C06RR14567 from the National Center for Research Resources, NIH.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

³ Personal communication with Dr. Milton L. Brown, Georgetown University.

Received 8/ 9/07; revised 11/ 2/07; accepted 1/11/08.