Binding and internalization of NGR-peptide-targeted liposomal doxorubicin (TVT-DOX) in CD13-expressing cells and its antitumor effects

Abstract

In an effort to develop new agents and molecular targets for the treatment of cancer, aspargine-glycine-arginine (NGR)-targeted liposomal doxorubicin (TVT-DOX) is being studied. The NGR peptide on the surface of liposomal doxorubicin (DOX) targets an aminopeptidase N (CD13) isoform, specific to the tumor neovasculature, making it a promising strategy. To further understand the molecular mechanisms of action, we investigated cell binding, kinetics of internalization as well as cytotoxicity of TVT-DOX in vitro. We demonstrate the specific binding of TVT-DOX to CD13-expressing endothelial [human umbilical vein endothelial cells (HUVEC) and Kaposi sarcoma-derived endothelial cells (SLK)] and tumor (fibrosarcoma, HT-1080) cells in vitro. Following binding, the drug was shown to internalize through the endosomal pathway, eventually leading to the localization of doxorubicin in cell nuclei. TVT-DOX showed selective toxicity toward CD13-expressing HUVEC, sparing the CD13-negative colon-cancer cells, HT-29. Additionally, the nontargeted counterpart of TVT-DOX, Caelyx, was less cytotoxic to the CD13-positive HUVECs demonstrating the advantages of NGR targeting in vitro. The antitumor activity of TVT-DOX was tested in nude mice bearing human prostate-cancer xenografts (PC3). A significant growth inhibition (up to 60%) of PC3 tumors in vivo was observed. Reduction of tumor vasculature following treatment with TVT-DOX was also apparent. We further compared the efficacies of TVT-DOX and free doxorubicin in the DOX-resistant colon-cancer model, HCT-116, and observed the more pronounced antitumor effects of the TVT-DOX formulation over free DOX. The potential utility of TVT-DOX in a variety of vascularized solid tumors is promising.

Advanced targeted therapies in cancer: Drug nanocarriers, the future of chemotherapy

“…This integrin is recognized by the peptide sequence arginine-glycine-aspartic acid (RGD) [523,524]. Wang et al [525] angiogenic vessels [532,533]. The use of a tumor-homing peptide, iRGD, an RGD peptide that contains a tumor penetrating peptide (CendR or C-end rule), results in an optimized delivery of anticancer drugs deeply to the tumors.…”

Lipid composition has significant effect on targeted drug delivery properties of NGR-modified liposomes

“…Consequently, PCs with different T m s were used to prepare NGR-modified liposomes, such as 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC) (Negussie et al, 2010;Dunne et al, 2011), hydrogenated soy posphatidylcholine (HSPC) (Pastorino et al, 2003;Garde et al, 2007;Takara et al, 2012) or soy posphatidylcholine (SPC) (Luo et al, 2013). The T m s of HSPC and DPPC are determined to be at 53 and 41 C, respectively.…”

New tumor-targeted nanosized delivery carrier for oligonucleotides: characteristics in vitro and in vivo

“…10 Traditional approaches to cancer therapy have focused on targeting and destroying cancer cells. 11 However, direct access to cancer cells is often restricted, leading to limited success of various agents, including DNA and RNA. To overcome this barrier, recent strategies have attempted to target the tumor vasculature instead of the cancer cells.…”