Systemic antiangiogenic activity of cationic poly-L-lysine dendrimer delays tumor growth

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 107; no. 9; pp. 3966 - 3971
• Main Authors: Al-Jamal, Khuloud T, Al-Jamal, Wafa' T, Akerman, Simon, Podesta, Jennifer E, Yilmazer, Açelya, Turton, John A, Bianco, Alberto, Vargesson, Neil, Kanthou, Chryso, Florence, Alexander T, Tozer, Gillian M, Kostarelos, Kostas
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 02-03-2010; National Acad Sciences
• Subjects: Amino acids; Angiogenesis; Angiogenesis Inhibitors - pharmacology; Animals; Biochemistry; Biological Sciences; Biotechnology; Cations; Cell Division - drug effects; Computer Science; Dendrimers; Dosage; Endothelial cells; Intravenous injections; Life Sciences; Medical treatment; Membranes; Mice; Mice, Inbred C57BL; Mice, SCID; Molecules; Neoplasms, Experimental - pathology; Physical Sciences; Polylysine - pharmacology; Protamines; Tumors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0908401107

This study describes the previously unreported intrinsic capacity of poly-L-lysine (PLL) sixth generation (G₆) dendrimer molecules to exhibit systemic antiangiogenic activity that could lead to solid tumor growth arrest. The PLL-dendrimer-inhibited tubule formation of SVEC4-10 murine endothelial cells and neovascularization in the chick embryo chick chorioallantoic membrane (CAM) assay. Intravenous administration of the PLL-dendrimer molecules into C57BL/6 mice inhibited vascularisation in Matrigel plugs implanted subcutaneously. Antiangiogenic activity was further evidenced using intravital microscopy of tumors grown within dorsal skinfold window chambers. Reduced vascularization of P22 rat sarcoma implanted in the dorsal window chamber of SCID mice was observed following tail vein administration (i.v.) of the PLL dendrimers. Also, the in vivo toxicological profile of the PLL-dendrimer molecules was shown to be safe at the dose regime studied. The antiangiogenic activity of the PLL dendrimer was further shown to be associated with significant suppression of B16F10 solid tumor volume and delayed tumor growth. Enhanced apoptosis/necrosis within tumors of PLL-dendrimer-treated animals only and reduction in the number of CD31 positive cells were observed in comparison to protamine treatment. This study suggests that PLL-dendrimer molecules can exhibit a systemic antiangiogenic activity that may be used for therapy of solid tumors, and in combination with their capacity to carry other therapeutic or diagnostic agents may potentially offer capabilities for the design of theranostic systems.