Abstract
Hepatocellular carcinomas are well-vascularized tumors; the endothelial cells in these tumors have a specific phenotype. Our aim was to develop a new approach for tumor-specific drug delivery with monoclonal antibody targeting of endothelial ligands. CD146, a molecule expressed on the endothelial surface of hepatocellular carcinoma, was identified as a promising candidate for targeting. In the present study, endothelial cells immediately captured circulating anti-CD146 (ME-9F1) antibody, while antibody binding in tumors was significantly higher than in hepatic endothelium. Macroscopically, after intravenous injection, there were no differences in the mean accumulation of anti-CD146 antibody in tumor compared to liver tissue , due to a compensating higher blood vessel density in the liver tissue. Additional blockade of nontumoral epitopes and intra-arterial administration, improved selective antibody capture in the tumor microvasculature and largely prevented antibody distribution in the lung and liver. The potential practical use of this approach was demonstrated by imaging of radionuclide-labeled ME-9F1 antibody, which showed excellent tumor-selective uptake. Our results provide a promising principle for the use of endothelial markers for intratumoral drug delivery. Tumor endothelium-based access might offer new opportunities for the imaging and therapy of hepatocellular carcinoma and other liver malignancies.
Highlights
The growth of hepatocellular carcinoma (HCC) strongly depends on the continuous development of blood vessels to form a tumor vascular system [1]
This approach utilizes the binding of specific ligands, such as antibodies, to markers expressed on the intraluminal surface of tumor endothelium
CD146 was approximately 2.6-fold overexpressed on mouse tumor endothelial cells compared to liver endothelial cells
Summary
The growth of hepatocellular carcinoma (HCC) strongly depends on the continuous development of blood vessels to form a tumor vascular system [1]. The tumor vasculature connects the tumor with the host and supplies the tumor with oxygen and nutrients. It drains away metabolic and other tumor products [2]. Because of its important biological role in tumor progression, the tumor vascular system represents a potential diagnostic and therapeutic target [3]. Anti-angiogenic therapy is directed against the formation of new tumor blood vessels and has been established as the therapy of choice against several solid tumors [4]. Vascular-targeted therapy includes different strategies that do not directly attack tumor blood vessels; instead, the tumor vascular system is used for imaging and tumor-specific drug delivery [3]
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