Abstract
In recent years, anti-angiogenic therapy has attracted much interest because it is a versatile approach to treating most types of tumors, and therefore would be expected to be applicable for various cancers. Severe adverse events in patients treated with currently available anti-angiogenic therapeutics have, however, been reported, and these are caused by their inhibitory effects in normal tissue. To achieve an efficient anti-angiogenic therapy with minimal toxicity, a drug delivery system (DDS) specific to tumor endothelial cells (TECs) is needed. Cyclic RGD (cRGD) is a well-known ligand against αVβ3 integrin that is expressed at high levels in the cell surface of TECs. To address this issue, we previously developed a cyclic RGD-equipped liposomal DDS (RGD-MEND) in which small interfering RNA (siRNA) was encapsulated. However, in the previous study, details of the preparation steps were not thoroughly examined. In this paper, to produce the most efficient delivery of therapeutic TECs, we explored optimum preparation conditions and components of the RGD-MEND. The cellular uptake and silencing ability of the RGD-MEND were investigated as a function of ligand density, poly(ethyleneglycol) linker length, and lipid composition. As a result, a knockdown efficiency that was five-fold higher than that of the previously reported one (ED50, from 4.0 to 0.75 mg/kg) was achieved.
Highlights
Since angiogenesis plays a pivotal role in cancer progression and metastasis, anti-angiogenic therapeutics are thought to be attractive for the development of new types of cancer therapy [1]
Anti-angiogenic therapeutics are relatively safe compared to traditional anti-cancer drugs, since they do not focus on cell-killing effects
We developed a tumor endothelial cells (TECs)-specific delivery system, the RGD-MEND, which was modified with a TEC-targeting ligand, cyclic RGD
Summary
Since angiogenesis plays a pivotal role in cancer progression and metastasis, anti-angiogenic therapeutics are thought to be attractive for the development of new types of cancer therapy [1].New vessel formation occurs when tumor tissue grows over 2 mm3 [2] and, anti-angiogenic therapy would be expected to be a new class of medicines for many types of cancers because of the universality of angiogenesis. Since angiogenesis plays a pivotal role in cancer progression and metastasis, anti-angiogenic therapeutics are thought to be attractive for the development of new types of cancer therapy [1]. Since VEGF cascades are involved in maintaining homeostasis for the entire body, recent studies revealed that the somatic inhibition of the VEGF cascade could induce severe adverse effects such as hypertension, bowel perforation, and arterial thromboembolisms [4,5]. For these reasons, tumor endothelial cell (TEC)-specific anti-angiogenic therapeutics are needed to achieve safe, effective cancer therapy
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