Abstract
Background: Cationic lipid complexes have been shown to predominantly target angiogenic endothelial cells of solid tumors. In order to realize a vascular targeting tumor therapy a novel compound was synthesized by encapsulation of the topoisomerase inhibitor camptothecin in cationic nanoparticles (EndoTag®-2). Here we studied tumor vascular targeting properties, antitumoral effects and mode of action of the novel compound. Material and methods: Tumor vascular targeting properties of fluorescently labelled EndoTag®-2 was investigated by in vivo microscopy using A-MEL-3 tumors grown in the dorsal skinfold chamber preparation. Therapeutic effects have been investigated in the s. c. LLC-1 carcinoma model and the L3.6pl human pancreatic cancer model implanted orthotopically in nude mice. Antivascular effects have been studied by histological investigation of tumor microvessel density and non invasive investigation of tumor blood flow by dynamic contrast enhanced MRI imaging (DCE-MRI). Results: EndoTag®-2 selectively targeted tumor microvessels as confirmed by quantitative fluorescence microscopy. Compared to controls EndoTag®-2 revealed remarkable antitumoral efficiency in s. c. LLC-1 carcinomas. Growth and metastasis of L3.6pl human pancreatic tumors was significantly inhibited by EndoTag®-2 treatment. Quantitative analysis of tumor microvessel density revealed significant reduction of microvessel density. DCE-MRI confirmed significant reduction of intratumoral vascular volume as well as tumor perfusion upon Endo- Tag®-2 treatment. Conclusion: Cationic lipid complexed camptothecin (EndoTag®-2) results in a markedly active antitumor agent based on an innovative vascular targeting approach.
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