Abstract
Angiogenesis is a critical process in numerous diseases, and intervention in neovascularization has therapeutic value in several disease settings, including ocular diseases, arthritis, and in tumor progression and metastatic spread. Various vascular targeting agents have been developed, including those that inhibit growth factor receptor tyrosine kinases, blocking antibodies that interfere with receptor signal transduction, and strategies that trap growth factor ligands. Limited anti-tumor efficacy studies have suggested that the targeted delivery of the human pro-apoptotic molecule Granzyme B to tumor cells has significant potential for cancer treatment. Here, we review biological vascular targeting agents, and describe a unique vascular targeting agent composed of Granzyme B and the VEGF receptor ligand VEGF121. The fusion protein GrB/VEGF121 demonstrates cytotoxicity at nanomolar or sub-nanomolar levels, excellent pharmacokinetic and efficacy profiles, and has significant therapeutic potential targeting tumor vasculature.
Highlights
We investigated the ability of Granzyme B (GrB)/VEGF121 to localize into primary tumors by the subcutaneous
We investigated the ability of GrB/VEGF121 to localize into primary tumors by the subcutaneous placement of human prostate PC-3 tumors into male nude mice
Mice received intravenous injections of either saline, GrB (15 mg/kg) or GrB/VEGF121 (11 or 27 mg/kg). (A) Treatment with GrB/VEGF121 caused a significant reduction in the growth of the primary tumor in nude mice. i.v.: intravenous injection. (B) The reduction in tumor growth is partially attributed to the reduction in the proliferation rate of the tumor cells. (C) In addition, tumor vasculature was significantly reduced upon GrB/VEGF121 treatment, with a greater than 14-fold reduction compared to mice treated with saline
Summary
Neovascularization is a normal process that occurs during growth and development, and critical during processes such as wound healing. Various elements of tumor neovascularization have been the focus of drug development strategies, and interventions at different points have been developed with varying levels of success in pre-clinical and clinical settings. Some such strategies include: inhibiting the downstream signaling of growth factor receptor tyrosine kinases [5,6,7], the development of blocking antibodies to attenuate receptor signal transduction [8,9,10,11], entrapment of growth factor ligands to prevent receptor activation [12,13,14], and the use of vascular-targeted photodynamic therapy [15]. Vascular targeting agents have been tested in combination with other therapies, such as radiotherapy [16]
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