Journal
MOLECULAR CANCER THERAPEUTICS
Volume 7, Issue 3, Pages 559-568Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-07-0548
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Funding
- NCI NIH HHS [2 P30 CA 51008] Funding Source: Medline
- NCRR NIH HHS [C06 RR 15768-01, 1 S10 RR 15768-01] Funding Source: Medline
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GMC-5-193 (GMC) is a novel anticancer small-molecule quinazolinone analogue with properties that include anti. microtubule 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-4351 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 similar to 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.
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